Archive for the ‘Hypogonadism’ Category

Dublin, May 31, 2024 (GLOBE NEWSWIRE) -- The "North America Hormone Replacement Therapy Market Report by Product, Route of Administration, Type of Disease, and Country 2024-2032" report has been added to ResearchAndMarkets.com's offering.

The North America hormone replacement therapy market size reached US$ 4.5 Billion in 2023. Looking forward, the market to reach US$ 6.9 Billion by 2032, exhibiting a growth rate (CAGR) of 4.9% during 2023-2032

This treatment is particularly favorable for patients who are experiencing growth hormone deficiency, women nearing menopause and older people suffering from hypogonadism. HRT is available in several forms such as gels, injections, implants, and skin and mouth patches (transdermal). However, it may not be suitable for patients that have a record of blood clots, liver disease and untreated high blood pressure.

North America hormone replacement therapy market is currently being driven by several factors. A surge in the incidences of hormone imbalance disorders, especially in the geriatric and neonatal populations, is spurring the demand for HRT in North America. In line with this, the rising need for new treatment options with better safety results is further catalyzing the market growth in the region.

Apart from this, increasing R&D activities for hormone replacement products is enhancing their quality and efficiency. Additionally, the increasing consumer awareness, coupled with the rising technological innovations, such as new gel-based formulations, have also spurred the demand for hormone replacement products in the region.

Key Questions Answered in This Report:

Key Attributes:

Report Insights

Key Market Segmentation:

Key Regions Analysed

Market by Product

Market by Route of Administration

Market by Type of Disease

For more information about this report visit https://www.researchandmarkets.com/r/ha9s07

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North America Hormone Replacement Therapy (HRT) Market Research 2024: A $6.9 Billion Industry by 2032, Driven ... - GlobeNewswire

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Testosterone deficiency in men with end stage renal disease and kidney transplantation: a narrative review ... - Nature.com

The following is a summary of Effect of Testosterone Replacement Therapy on Sexual Function and Hypogonadal Symptoms in Men with Hypogonadism, published in the February 2024 issue of Endocrinology by Pencina, et al.

For a Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study, researchers sought to assess the efficacy of testosterone replacement therapy (TRT) in improving sexual function and hypogonadal symptoms in men with hypogonadism, with a focus on whether these effects are sustained beyond 12 months. The Sexual Function Study, nested within the TRAVERSE trial, specifically evaluated the impact of TRT on sexual activity, hypogonadal symptoms, libido, and erectile function among men with low libido.

Among 5,204 men aged 45-80 years with two testosterone concentrations <300 nag/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk enrolled in the TRAVERSE trial, 1,161 participants with low libido were included in the Sexual Function Study. Of these, 587 were randomized to receive 1.62% testosterone gel and 574 to placebo gel for their participation. The primary outcome was the change from baseline in sexual activity score, with secondary outcomes including hypogonadal symptoms, erectile function, and sexual desire.

TRT was associated with a significantly greater improvement in sexual activity compared to placebo, with a sustained treatment effect observed at 24 months. Additionally, TRT improved hypogonadal symptoms and sexual desire, although it did not significantly affect erectile function compared to placebo.

In middle-aged and older men with hypogonadism and low libido, TRT for 2 years effectively improved sexual activity, hypogonadal symptoms, and sexual desire. However, it did not demonstrate significant improvements in erectile function compared to placebo.

Reference: academic.oup.com/jcem/article-abstract/109/2/569/7244351

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Enhancing Quality of Life: Testosterone Replacement Therapy for Hypogonadal Men - Physician's Weekly

Testosterone replacement therapy may not increase risk of prostate cancer among men with hypogonadism  Medical Dialogues

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Testosterone replacement therapy may not increase risk of prostate cancer among men with hypogonadism - Medical Dialogues

BackWhat Is It, Causes, Signs and Symptoms, and More

Author: Anna Hernndez, MD

Editors: Alyssa Haag, Emily Miao, PharmD, Kelsey LaFayette, DNP, RN

Illustrator: Jessica Reynolds, MS

Copyeditor: Sadia Zaman, MBBS, BSc

Hypogonadism is a clinical syndrome that occurs when the gonadstestes and ovariesproduce low levels of sex hormones due to a disruption of the hypothalamic-pituitary-gonadal (HPG) axis.

There are two main types of hypogonadism, primary and secondary. Primary hypogonadism is caused by dysfunction of the gonads, and can be acquired or congenital. Acquired causes include radiation therapy, chemotherapy, autoimmunity, trauma to the gonads, and certain infections, like mumps orchitis. On the other hand, congenital causes include genetic disorders, like Klinefelter syndrome or Turner syndrome, both of which affect gonadal function. Regardless of the cause, the result is a decrease or complete absence of sex hormones, which means there is no negative feedback on the hypothalamic-pituitary-gonadal axis. This leads to an overproduction of the LH and FSH gonadotropins, thus giving primary hypogonadism its other name, hypergonadotropic hypogonadism.

Signs and symptoms of hypogonadism vary depending on whether hypogonadism occurs before or after puberty. The most common presenting feature of hypogonadism in teenagers is a delay in puberty, which generally occurs when puberty has not started by age 13 in those assigned female at birth and age 14 in those assigned male at birth. Other clinical features of hypogonadism include a high-pitched voice, sparse body hair, poorly developed muscles, small or underdeveloped genitals, and short stature due to delayed epiphyseal closure. Another presenting feature can be primary amenorrhea, which is when an individual hasnt had their first menstruation by the age of 13 to 15.

Diagnosis of hypogonadism begins with a thorough medical history and physical exam, including assessment using the Tanner scale. The Tanner scale, or Tanner stages, consists of a predictable set of steps that individuals go through as they develop primary and secondary sex characteristics and become sexually mature. This scale centers on two, independent criteria: the appearance of pubic hair; and the increase in testicular volume and penile size and length in those assigned male at birth or with breast development in those assigned female at birth.

Treatment of hypogonadism is directed at addressing the underlying cause, when possible. In most cases, hypogonadism can be managed with hormone replacement therapy to ensure the onset and progression of puberty, as well as improve the symptoms of hypogonadism.

Certain cases of hypogonadism are transient and can be reversed, especially if they are a result of a treatable underlying disorder, such as malnutrition, excessive exercise, or stress. In addition, there have been cases of idiopathic hypogonadotropic hypogonadism that have reversed over time, although the exact reason why is still unknown.

Hypogonadism refers to a clinical syndrome that results in low levels of sex hormones. There are two types of hypogonadism: primary and secondary. Signs and symptoms of hypogonadism depend on the time of onset, and can include delayed puberty, primary amenorrhea, changes in mood and energy, infertility, decreased libido, and erectile dysfunction. Diagnosis of hypogonadism is based on the clinical manifestations along with lab tests to assess the levels of sex hormones in the body. Treatment involves long-term hormone replacement therapy and fertility treatments, as well as treatment of the underlying cause of hypogonadism, when possible.

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Hypogonadism: What Is It, Causes, Signs and Symptoms, and More - Osmosis

Continuing Education Activity

Male hypogonadism, acquired or congenital, can be caused by defects that interfere with the hypothalamic-pituitary-testicular axis. It is essential to distinguish between primary hypogonadism (which originates in the testes) and secondary hypogonadism (which originates in the hypothalamus or pituitary gland). Symptoms highly suggestive of hypogonadism include decreased spontaneous erections, decreased nocturnal penile tumescence, decreased libido, and reduced testicular volume. This activity reviews the evaluation and management of male hypogonadism and describes which patients are most likely to benefit from screening. This activity highlights the role of the interprofessional team in improving care for patients with male hypogonadism.

Objectives:

Describe the etiology of male hypogonadism.

Explain the pathophysiology of male hypogonadism.

Review the evaluation of male hypogonadism.

Describe interprofessional team strategies for improving care coordination and communication to patients with male hypogonadism.

Nintey-five percent of the total testosterone in males is synthesized in the Leydig cells of the testis.Defects, whether acquired or congenital, that interefere with interactions in the hypothalamic-pituitary-testicular axis cancause male hypogonadism It is essential to distinguish between primary hypogonadism (which originates in the testes) and secondary hypogonadism (which originates in the hypothalamus or pituitary). Symptoms highly suggestive of hypogonadism include decreased spontaneous erections, decreased nocturnal penile tumescence, decreased libido, and reduced testicular volume. The normal range for early morning testosterone in amale is between 300 ng/dL to 1000 ng/dL[1]. Hypogonadism is diagnosed when the morning serum testosterone level is less than 300 ng/dL. However, clinicaljudgmentcan be exercised in the diagnosis of hypogonadismfor patients with persistentsymptoms of testosterone deficiency despite having testosterone levels are in the normal range [2]. Of note, total testosterone less than 405.9 ng/dL is below the fifthpercentile[3]. Elderly males should aim for testosterone levels between 500 and 800 ng/dL while young adults should aim for testosterone levels between 600 and 900 ng/dL.

Hypogonadism can be due to congenital or acquired causes. Ambiguous genitalia, micropenis, and bilateral cryptorchidism are all signs of testosterone deficiency in pre-pubertal males. Karyotype testing is done in young adults to rule out conditions such as Turner syndrome and Klinefelter syndrome which can result in testosterone deficiency. Some causes of primary hypogonadism include Klinefelters syndrome, undescended testicles, mumps orchitis, hemochromatosis, cancer treatment, and normal aging. Causes of secondary hypogonadism include Kallman syndrome, pituitary disorders, HIV, obesity, surgery, trauma, and stress-induced hypogonadism[4].

Hypogonadism is often under-reported. According to some studies approximately 40% of men over the age of 45 and 50% of men in their 80s are hypogonadal[5][6]. Testosterone levels have been found to decrease by 100 ng/dL every ten years[7]. There appears to be no relationship between racial and ethnic groups with hypogonadism.

Testosterone production by testicularLeydig cells depends on stimulationfrom the anterior pituitary gland which secretespulses of luteinizing hormone (LH) into thecirculation.When LH binds toits receptors onLeydig cells, it causes cAMP levelsto rise. Increased levels ofcAMPdrives the expression of two proteins:StAR (the steroidogenic acute regulatory protein) andCYP11A1 (the cholesterol sidechain clevage enzyme). StAR promotes the transfer of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane while CYP11A1 promotes the conversion of cholesterol to pregnenolone, the precursor of all steroid hormones. Pregnenolone can undergo 17 alpha-hydroxylation to 17 OH pregnenolone which is converted to DHEA, dehydroepiandrosterone[8]. DHEA is then converted into androstenediolin orderto maketestosterone.Primary hypogonadism is when the testicular steroidogenesisis insufficient to synthesis adequate levels oftestosterone while secondary hypogonadism is when signaling to the testis(eitherfrom thepituitary, through LH,or from the hypothalamus, through GnRH)is unable to stimulatesufficient Leydig cell testosterone production.

Symptoms highly suggestive of androgen deficiency in men include reduced sexual desire, decreased spontaneous erections, loss of axillary and pubic hair, declining testicular volume, hot flashes, low or zero sperm count. Other less suggestive symptoms include depressed mood, poor concentration, increased body fat, decreased physical performance, reduced muscle mass.

Population screeningis not recommended, butpatients with either HIV, end-stagerenal disease, type 2 diabetes, infertility, severe COPD,orosteoporosisshould be screened[9].The Androgen Deficiency in Aging Male (ADAM) test is the initial step in diagnosis; it consists of a 10-item questionnaire toidentify men who exhibit signs oftestosterone deficiency[10]. Initial laboratory testing should include two early morning (8 am-10 am) measurements of serum testosterone[11]. Ifboth levels are reduced, further testing including FSH (follicle stimulating hormone), LH, prolactin, TSH (thyroid stimulating hormone), free T4 (thyroxine), vitamin D, complete blood count, comprehensive metabolic panel, iron, transferrin, and cortisol are indicated. It is also important to measure sex hormone binding globulin (SHBG) in orderto calculate the bioavailable testosterone which can be affected by obesity, type 2 diabetes, hypothyroidism, and liver disease.

There are several options for testosterone replacement including oral, buccal, transdermal (gel, patch, solution, pellet), and intramuscular injections (add reference: Surampudi, P. et al. An Update on Male Hypogonadism Therapy. Expert Opin Pharmacother 15(9):1247-1264, 2014).Among these transdermal gels and intramuscular injections are the most widely used in the US.Testosterone gels are generallyrecommended due to patient preference, cost, convenience, and insurance coverage. The primary advantage of gels is the maintenance of stable serum testosterone concentrations resulting in stable libido, energy, and mood. There are various commercial prescription testosterone gel products, in varying concentrations. Gels should be applied toshoulder, upper arms, or abdomen and shouldn't be applied to the scrotum.Miller and colleagues (9) showed that the bioavailability of testosterone gel is 30 percent lower when applied to the abdomen compared to the armsor shoulders[12]. It is generally recommended that intramuscular injections of testosteronewith testosterone enanthateor testosterone cypionate be given 50 to 100mg doses every week or 100 to 200mg doses every two weeks. In 2014, the FDA approved an extra-long acting intramuscular injectable form of testosterone called testosterone undecanoate which is administered at an initial dose of 750mg followed by a second dose four weeks laterwith subsequent dosesgiven at ten week intervals. Testosterone undecanoate is not used as a first-line agent but ratherin patients that dont have access to other forms of treatment.

Contraindications to androgen replacement therapy include a history of breast cancer, prostate cancer, uncontrolled heart failure, untreated obstructive sleep apnea,a pre-treatmenthematocrit (Hct) over 48%, palpable undiagnosed prostate nodules, an elevated prostate specific antigen (PSA) above 4ng/mL, or an elevated PSA level above 3ng/mL in high-risk patients including African Americans as well as menthat havea first-degree relative with prostate cancer[9].

Monitoring:

Pretreatment: Hgb, Hct, DRE (digital rectal exam), PSA level, two early morning testosterone levels, consider DEXA scan

One month after initiating treatment: morning testosterone level

3 to 6 months after from the start of therapy during the first year: morning testosterone level, liver function tests (LFTs), lipid profile, PSA, DRE, Hgb, Hct

Annually after the first year: morning testosterone level, LFTs, lipid profile, DRE, PSA, estradiol,Hgb, and Hct.

Differential diagnoses include hyperprolactinemia, congenital adrenal hyperplasia, anorexia nervosa, androgen insensitivity syndrome, malnutrition, Turner syndrome, Klinefelter syndrome, and 5-alpha-reductase deficiency.Kallman syndrome should be ruled out in males complaining of anosmia or hyposmia. Pituitary gland masses need to be ruled out in patients complaining of visual disturbances.

It is important for nurses, physicians, and pharmacists to review the risks and benefits of therapy and to be aware of the contraindications to testosterone therapy. There are conflicting trials on the cardiovascular risks of testosterone, most notably the TOM (Testosterone in Older Men) trial and the TEAAM(Testosterone's Effects on Atherosclerosis Progression in Aging Men) trial.

Outcomes: The TOM trial found that the application of testosterone gel daily after six monthswas associated with an increased incidence of cardiovascular events[13]. The TOM trial used a sample size of 209 men with no monitoring of serum testosterone levels.Recently, the TEAAM trial published in 2015 followed 308 men over three years and found that testosterone administration resulted in no difference in cardiovascular risk[14].A randomized, double-blind, placebo-controlled, parallel study found that testosterone undecanoate resulted in reduced fasting glucose, waist circumference, and improved carotid intima-mediathickness and high sensitivityC-reactive protein after 12 weeks of treatment[15]. (Level V)

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Hypogonadism - StatPearls - NCBI Bookshelf

Abstract

Male hypogonadism is a condition in which the body does not produce enough of the testosterone hormone; the hormone that plays a key role in masculine growth and development during puberty. There is a clear need to increase the awareness of hypogonadism throughout the medical profession, especially in primary care physicians who are usually the first port of call for the patient. Hypogonadism can significantly reduce the quality of life and has resulted in the loss of livelihood and separation of couples, leading to divorce. It is also important for doctors to recognize that testosterone is not just a sex hormone. There is an important research being published to demonstrate that testosterone may have key actions on metabolism, on the vasculature, and on brain function, in addition to its well-known effects on bone and body composition. This article has been used as an introduction for the need to develop sensitive and reliable assays for sex hormones and for symptoms and treatment of hypogonadism.

Keywords: Male hypogonadism, pituitary, sex hormone, testosterone, testis

Hypogonadism is a medical term for decreased functional activity of the gonads. The gonads (ovaries or testes) produce hormones (testosterone, estradiol, antimullerian hormone, progesterone, inhibin B, activin) and gametes (eggs or sperm).[1] Male hypogonadism is characterized by a deficiency in testosterone a critical hormone for sexual, cognitive, and body function and development. Clinically low testosterone levels can lead to the absence of secondary sex characteristics, infertility, muscle wasting, and other abnormalities. Low testosterone levels may be due to testicular, hypothalamic, or pituitary abnormalities. In individuals who also present with clinical signs and symptoms, clinical guidelines recommend treatment with testosterone replacement therapy.

There are two basic types of hypogonadism that exist:

Primary: This type of hypogonadism also known as primary testicular failure originates from a problem in the testicles.

Secondary: This type of hypogonadism indicates a problem in the hypothalamus or the pituitary gland parts of the brain that signal the testicles to produce testosterone. The hypothalamus produces the gonadotropin releasing hormone, which signals the pituitary gland to make the follicle-stimulating hormone (FSH) and luteinizing hormone. The luteinizing hormone then signals the testes to produce testosterone. Either type of hypogonadism may be caused by an inherited (congenital) trait or something that happens later in life (acquired), such as an injury or an infection.

Common causes of primary hypogonadism include:

Klinefelter's Syndrome: This condition results from a congenital abnormality of the sex chromosomes, X and Y. A male normally has one X and one Y chromosome. In Klinefelter's syndrome, two or more X chromosomes are present in addition to one Y chromosome. The Y chromosome contains the genetic material that determines the sex of a child and the related development. The extra X chromosome that occurs in Klinefelter's syndrome causes abnormal development of the testicles, which in turn results in the underproduction of testosterone.

Before birth, the testicles develop inside the abdomen and normally move down into their permanent place in the scrotum. Sometimes, one or both of the testicles may not descend at birth. This condition often corrects itself within the first few years of life without treatment. If not corrected in early childhood, it may lead to malfunction of the testicles and reduced production of testosterone.

If a mumps infection involving the testicles in addition to the salivary glands (mumps orchitis) occurs during adolescence or adulthood, long-term testicular damage may occur. This may affect normal testicular function and testosterone production.

Too much iron in the blood can cause testicular failure or pituitary gland dysfunction, affecting testosterone production.

Because of their location outside the abdomen, the testicles are prone to injury. Damage to normally developed testicles can cause hypogonadism. Damage to one testicle may not impair testosterone production.

Chemotherapy or radiation therapy for the treatment of cancer can interfere with testosterone and sperm production. The effects of both treatments are often temporary, but permanent infertility may occur. Although many men regain their fertility within a few months after the treatment ends, preserving sperm before starting cancer therapy is an option that many men consider. Howell et al. reported that hypogonadism was seen in 30% of the men with cancer and 90% of these gentlemen had germinal epithelial failure.[2]

Older men generally have lower testosterone levels than younger men do. As men age, there's a slow and continuous decrease in testosterone production. The rate that testosterone declines varies greatly among men. As many as 30% of men older than 75 have a testosterone level that is below normal, according to the American Association of Clinical Endocrinologists. Whether or not treatment is necessary remains a matter of debate.[3]

In secondary hypogonadism, the testicles are normal, but function improperly due to a problem with the pituitary or hypothalamus. A number of conditions can cause secondary hypogonadism, including:

Abnormal development of the hypothalamus the area of the brain that controls the secretion of pituitary hormones can cause hypogonadism. This abnormality is also associated with the impaired development of the ability to smell (anosmia).

An abnormality in the pituitary gland can impair the release of hormones from the pituitary gland to the testicles, affecting normal testosterone production. A pituitary tumor or other type of brain tumor located near the pituitary gland may cause testosterone or other hormone deficiencies. Also, the treatment for a brain tumor such as surgery or radiation therapy may impair pituitary function and cause hypogonadism.

Certain inflammatory diseases such as sarcoidosis, Histiocytosis, and tuberculosis involve the hypothalmus and pituitary gland and can affect testosterone production, causing hypogonadism.

This virus can cause low levels of testosterone by affecting the hypothalamus, the pituitary, and the testes.

The use of certain drugs, such as, opiate pain medications and some hormones, can affect testosterone production.[4]

Being significantly overweight at any age may be linked to hypogonadism.

Stress, excessive physical activity, and weight loss have all been associated with hypogonadism. Some have attributed this to stress-induced hypercortisolism, which would suppress hypothalamic function.[5]

Throughout the male lifespan, testosterone plays a critical role in sexual, cognitive, and body development. During fetal development, testosterone aids in the determination of sex. The most visible effects of rising testosterone levels begin in the prepubertal stage. During this time, body odor develops, oiliness of the skin and hair increase, acne develops, accelerated growth spurts occur, and pubic, early facial, and axillary hair grows. In men, the pubertal effects include enlargement of the sebaceous glands, penis enlargement, increased libido, increased frequency of erections, increased muscle mass, deepening of voice, increased height, bone maturations, loss of scalp hair, and growth of facial, chest, leg, and axillary hair. Even as adults, the effects of testosterone are visible as libido, penile erections, aggression, and mental and physical energy.

The cerebral cortex the layer of the brain often referred to as the gray matter is the most highly developed portion of the human brain. This portion of the brain, encompassing about two-thirds of the brain mass, is responsible for the information processing in the brain. It is within this portion of the brain that testosterone production begins. The cerebral cortex signals the hypothalamus to stimulate production of testosterone. To do this, the hypothalamus releases the gonadotropin-releasing hormone in a pulsatile fashion, which stimulates the pituitary gland the portion of the brain responsible for hormones involved in the regulation of growth, thyroid function, blood pressure, and other essential body functions. Once stimulated by the gonadotropin-releasing hormone, the pituitary gland produces the follicle-stimulating hormone and the luteinizing hormone. Once released into the bloodstream, the luteinizing hormone triggers activity in the Leydig cells in the testes. In the Leydig cells, cholesterol is converted to testosterone. When the testosterone levels are sufficient, the pituitary gland slows the release of the luteinizing hormone via a negative feedback mechanism, thereby, slowing testosterone production. With such a complex process, many potential problems can lead to low testosterone levels. Any changes in the testicles, hypothalamus or pituitary gland can result in hypogonadism. Such changes can be congenital or acquired, temporary, or permanent.

Recent studies have found that testosterone production slowly decreases as a result of aging, although the rate of decline varies. Unlike women who experience a rapid decline in hormone levels during menopause, men experience a slow, continuous decline over time. The Baltimore Longitudinal Study of Aging reported that approximately 20% of men in their 60s and 50% of men in their 80s are hypogonadal.[6] The New Mexico Aging Process Study showed a decrease in serum testosterone of 110 ng/dL every 10 years.[7] As hormone levels decline slowly, this type of hypogonadism is sometimes referred to as the partial androgen deficiency of the aging male (PADAM). With the growing elderly population, the incidence of PADAM may increase over the next few decades.

Regardless of the age or comorbid conditions, obesity is associated with hypogonadism. The Baltimore Longitudinal Study of Aging found that testosterone decreased by 10 ng/dL per 1-kg/m2 increase in body mass index.[6] Another study also showed reduced testosterone levels in men with increased total abdominal adiposity.[8] The proposed causes for the effects of obesity on testosterone level include increased clearance or aromatization of testosterone in the adipose tissue and increased formation of inflammatory cytokines, which hinder the secretion of the gonadotropin-releasing hormone.[9] Similar to the projections for an aging population, the increasing incidence of obesity may lead to an increased incidence of secondary hypogonadism. When the risk factors of obesity and age are removed, diabetes mellitus still remains an independent risk factor for hypogonadism. Although diabetes mellitusrelated hypogonadism was previously thought to be associated with testicular failure, study results show one-third of diabetic men had low testosterone levels, but also had low pituitary hormone levels.[10] Population projections expect the number of cases of diabetes mellitus to rise from 171 million in 2000 to 366 million in 2030.[11] This drastic increase in cases will impact the prevalence of hypogonadism as well. Certain medications are shown to reduce testosterone production. Among the medications known to alter the hypothalamic-pituitary-gonadal axis are spironolactone, corticosteroids, ketoconazole, ethanol, anticonvulsants, immunosuppressants, opiates, psychotropic medications, and hormones.

Hypogonadism is characterized by serum testosterone levels < 300 ng/dL in combination with at least one clinical sign or symptom. Signs of hypogonadism include absence or regression of secondary sex characteristics, anemia, muscle wasting, reduced bone mass or bone mineral density, oligospermia, and abdominal adiposity. Symptoms of post pubescent hypogonadism include sexual dysfunction (erectile dysfunction, reduced libido, diminished penile sensation, difficulty attaining orgasm, and reduced ejaculate), reduced energy and stamina, depressed mood, increased irritability, difficulty concentrating, changes in cholesterol levels, anemia, osteoporosis, and hot flushes. In the prepubertal male, if treatment is not initiated, signs and symptoms include sparse body hair and delayed epiphyseal closure.

Early diagnosis and treatment can reduce risks associated with hypogonadism. Early detection in young boys can help to prevent problems due to delayed puberty. Early diagnosis in men helps protect against the development of osteoporosis and other conditions. The diagnosis of hypogonadism is based on symptoms and blood work, particularly on testosterone levels. Often the first step toward diagnosis is the Androgen Deficiency in Aging Male (ADAM) test a 10 item questionnaire intended to identify men who exhibit signs of low testosterone. Testosterone levels vary throughout the day and are generally highest in the morning, so blood levels are typically drawn early in the morning. If low testosterone levels are confirmed, further testing is done, to identify if the cause is testicular, hypothalamic, or pituitary. These tests may include hormone testing, semen analysis, pituitary imaging, testicular biopsy, and genetic studies. Once the treatment starts, the patient may continue to have testosterone levels drawn to determine if the medication is helping to produce adequate testosterone levels.

Testosterone replacement therapy is the primary treatment option for hypogonadism. Ideally, the therapy should provide physiological testosterone levels, typically in the range of 300 to 800 ng/dL. According to the guidelines from the American Association of Clinical Endocrinologists,[12] updated in 2002, the goals of therapy are to:

(1)

Restore sexual function, libido, well-being, and behavior

(2)

Produce and maintain virilization

(3)

Optimize bone density and prevent osteoporosis

(4)

In elderly men, possibly normalize growth hormone levels

(5)

Potentially affect the risk of cardiovascular disease

(6)

To achieve these goals, several testosterone delivery systems are currently available in the market. Clinical guidelines published in 2006, by the Endocrine Society, recommend reserving treatment for those patients with clinical symptoms, rather than for those with just low testosterone levels.

Transdermal testosterone patches are available in India under the brand name Androderm. Transdermal patches deliver continuous levels of testosterone over a 24-hour period. Application site reactions account for the majority of adverse effects associated with transdermal patches, with elderly men proving particularly prone to skin irritation. Local reactions include pruritus, blistering under the patch, erythema, vesicle formation, indurations, and allergic contact dermatitis. Approximately 10% of the patients discontinue patch therapy due to skin reactions.[14] In one study, 60% of the subjects discontinued the patch between weeks four and eight due to skin irritation.[15] A small percentage of patients may also experience headache, depression, and gastrointestinal (GI) bleeding. Some patients report that the patch easily falls off and is difficult to remove from the package without good dexterity. Transdermal patches are more expensive than injections, but the convenience of use and maintenance of normal diurnal testosterone levels are advantageous. Some patients report that the patch is noisy and therefore they feel stigmatized by its presence.

Currently, two topical testosterone gels Androgel and Testim, are available in India. Application in the morning allows for testosterone concentrations that follow the normal circadian pattern. Topical testosterone gels also provide longer-lasting elevations in serum testosterone, compared to transdermal patches.[16] Similar to patches, testosterone delivered via gels does not undergo first-pass metabolism. Adverse effects associated with therapy include headache, hot flushes, insomnia, increased blood pressure, acne, emotional labiality, and nervousness. Although application site reactions occur, skin irritation is approximately 10 times less frequent with gels than with transdermal patches.[17] Advantages associated with topical gel include maintenance of normal diurnal testosterone levels and documented increases in bone density.[18] Potential problems associated with the gel are the potential for transfer of the gel from person to person and the cost.

Buccal testosterone tablets, marketed as Striant, release testosterone in a pulsatile manner, are similar to endogenous secretion. With this route, the peak testosterone levels are rapidly achieved and a steady state is reached by the second dose following twice-daily dosing. Similar to gel and transdermal products, buccal administration avoids first-pass metabolism. Food and beverage do not alter drug absorption. Although well-tolerated, transient gum irritation and a bitter taste are the chief adverse effects associated with this route. Gum irritation tends to resolve within the first week. Other adverse effects include dry mouth, toothache, and stomatitis. Some patients find the buccal tablet uncomfortable and report concern about the tablet shifting in the mouth while talking.

Testosterone has also been formulated into an implantable pellet, marketed as Testopel. This surgically implanted pellet slowly releases testosterone via zero-order kinetics over many months (up to six months), although peak testosterone levels are achieved within 30 minutes. The chief complaints associated with this formulation are pellet extrusion, minor bleeding, and fibrosis at the site.

Intramuscular formulations are also available, sold as Depo-Testosterone (testosterone cypionate) and Delatestryl (testosterone enanthate). The testosterone is suspended in oil to prolong absorption. Peak levels occur within 72 hours of administration, but intramuscular administration is associated with the most variable pharmacokinetics of all the formulations. In the first few days after administration, supraphysiological testosterone levels are achieved, followed by subphysiological levels near the end of the dosing interval. Such fluctuations, are often associated with wide variations in mood, energy, and sexual function, and prove distressing to many patients. To reduce fluctuations, lower doses and shorter dosing intervals (two weeks) are often used. Injection site reactions are also common, but are rarely the reason for discontinuation of therapy. Despite the fluctuations in testosterone levels, intramuscular injections provide a cost-effective option and the convenience of two- to four-week dosing intervals. Disadvantages associated with injections include visits to the doctor's office, visits for dose administration, and lack of physiological testosterone patterns.

Although not currently available in the India, oral testosterone tablets, under the brand name Andriol, are available in other countries. In India, Android and Testroid both methyl testosterone products are FDA approved oral formulations. Although relatively inexpensive, oral products undergo extensive first-pass metabolism and therefore require multiple daily doses. Oral products are associated with elevated liver enzymes, GI intolerance, acne, and gynecomastia. Regardless of the treatment option, patients should be aware of the risks associated with testosterone therapy, including:

Worsening of the prostatic hypertrophy

Increased risk of prostate cancer

Lower sperm count with large doses

Swelling of ankles, feet, or body, with or without heart failure

Gynecomastia

Sleep apnea

Blood clots

Patients should be educated on the signs and symptoms of these adverse effects and instructed to notify their doctor if any of these occur.

Hypogonadism affects men of all ages, either through congenital or acquired causes. For patients who have clinical symptoms associated with their low testosterone levels, treatment is essential for the prevention of sexual, cognitive, and bodily changes. A variety of treatment options are available, utilizing different dosage formulations, and providing patients with choices that best meet their needs. Therefore, there is a clear need to increase the awareness of hypogonadism throughout the medical profession, especially in primary care physicians who are usually the first port of call for the patient.

In summary, there is a need for doctors to have an awareness of hypogonadism as a common clinical condition. Key triggers for the physician to consider investigating for hypogonadism are reduced libido, fatigue, osteoporosis and fractures, and erectile dysfunction.

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Male hypogonadism: Symptoms and treatment - PMC - PubMed Central (PMC)

Some men develop depression,loss of sex drive, erectile dysfunction, and other physical and emotional symptomswhen they reach their late 40s to early 50s.

Other symptoms common in men this ageare:

These symptoms can interfere with everyday life and happiness, so it's important tofind the underlying cause and work out what can be done to resolve it.

The "male menopause" (sometimes called the andropause) is an unhelpful term sometimes used in the media.

This label ismisleading because it suggests the symptoms are the result of a suddendrop in testosterone in middle age, similar to what occurs in the female menopause. This is not true.

Although testosterone levels fall as men age, the decline is steady at about 1% a year from around the age of 30 to 40,and this is unlikely to cause any problems in itself.

A testosterone deficiency that develops later in life, also known as late-onset hypogonadism, can sometimesbe responsible for these symptoms, but in many cases the symptoms are nothing to do withhormones.

Lifestyle factors or psychological problems can also be responsible for many of these symptoms.

For example,erectile dysfunction,low sex driveandmood swingsmay bethe result of:

There are alsophysical causes of erectile dysfunction, such as smoking or heart problems, which may happen alongside any psychological cause.

Psychological problems are typically brought on by workor relationship issues,money problems or worrying about ageing parents.

A "midlife crisis" can also be responsible. Thiscan happen when men think they have reached life's halfway stage.

Anxieties over what they have accomplished so far, either in their job or personal life, can lead to a period of depression.

Other possible causes of the "male menopause" include:

In some cases, where lifestyle or psychological problems do not seem to be responsible, the symptoms of the "male menopause" may bethe result ofhypogonadism, wherethe testes produce few or no hormones.

Hypogonadism issometimes present from birth,which can cause symptoms like delayed puberty and small testes.

Hypogonadism can also occasionallydevelop later in life, particularly in men who are obese or have type 2 diabetes.

This is known aslate-onset hypogonadism and can cause the "male menopause" symptoms.

But this is an uncommon and specific medical condition that's not a normal part of ageing.

A diagnosis oflate-onset hypogonadism can usually be made based on your symptoms and the results of blood testsused tomeasure your testosterone levels.

If you're experiencing any of these symptoms, see your GP. They'll ask about your work and personal life to see if your symptoms may be caused by a mental health issue, such as stress or anxiety.

If stress or anxiety are affecting you, you may benefit from medication or a talking therapy, such as cognitive behavioural therapy (CBT).

Exercise and relaxation can also help.

Read about:

Your GP may also order ablood test to measure your testosterone levels.

If the results suggest you have a testosterone deficiency, you may be referred to an endocrinologist, a specialist in hormone problems.

If the specialist confirms this diagnosis,youmay be offered testosterone replacementto correct the hormone deficiency, which should relieve your symptoms.

This treatment may be given as an injection or a gel.

Page last reviewed: 13 October 2022Next review due: 13 October 2025

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The 'male menopause' - NHS

Rev Urol. 2004; 6(Suppl 6): S3S8.

Auxilium Pharmaceuticals, Inc., Norristown, PA

Hypogonadism can be of hypothalamic-pituitary origin or of testicular origin, or a combination of both, which is increasingly common in the aging male population. In the postpubertal male, testosterone replacement therapy can be used to treat the signs and symptoms of low testosterone, which include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, loss of muscle mass and strength, and some regression of secondary sexual characteristics. Before initiation of testosterone replacement therapy, an examination of the prostate and assessment of prostate symptoms should be performed, and both the hematocrit and lipid profile should be measured. Absolute contraindications to testosterone replacement therapy are prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation.

Key words: Hypogonadism, Testosterone replacement therapy, Serum hormone-binding globulin, Luteinizing hormone, Follicle-stimulating hormone

Hypogonadism is a lack of testosterone in male patients and can be of central (hypothalamic or pituitary) or testicular origin, or a combination of both. Hypogonadism in male patients with testicular failure due to genetic disorders (eg, Klinefelters syndrome), orchitis, trauma, radiation, chemotherapy, or undescended testes, is known as hypergonadotropic hypogonadism or primary hypogonadism. Hypogonadism in male patients with gonadotropin deficiency or dysfunction as a result of disease or damage to the hypothalamic-pituitary axis is known as hypogonadotropic hypogonadism, central hypogonadism, or secondary hypogonadism. This might be due to Kallmanns syndrome, tumor, trauma, radiation, sarcoidosis, or tuberculosis. In addition, men older than 50 years might have low testosterone levels with functional abnormalities at multiple levels of the hypothalamic-pituitary-testicular axis.1,2,3

The prevalence of hypogonadism has increased in recent years. It has been reported that 12%, 19%, 28%, and 49% of men greater than 50, 60, 70, or 80 years of age, respectively, fit the criteria of hypogonadism.4

During puberty, testosterone is required for the development of male secondary sexual characteristics, stimulation of sexual behavior and function, and initiation of sperm production.5,6 In adult males, testosterone is involved in maintaining muscle mass and strength, fat distribution, bone mass, red blood cell production, male hair pattern, libido and potency, and spermatogenesis.13,5,6

In men, the major gonadal steroid hormone is testosterone. Testosterone circulates in 3 major forms: unbound, or free, testosterone; tightly bound testosterone, which is bound to sex hormone-binding globulin (SHBG); and weakly bound testosterone, which is bound to albumin. Only free and weakly bound testosterone is bioavailable or able to bind to the androgen receptor.2,3

In males, serum testosterone levels show a circadian variation, with the highest levels in the morning and lowest levels in the late afternoon. In young men, the variation in testosterone levels is approximately 35%. Although the normal range for serum testosterone might vary between different laboratories, the normal range for early morning total testosterone in healthy adult males is approximately 300 ng/dL to 1000 ng/dL.7,8

To determine whether a patient is testosterone deficient, a clinician must consider clinical signs and symptoms in conjunction with laboratory values. The initial clinical picture will vary depending on the age of the patient at the onset of the disorder.

In the normal male, the start of puberty is apparent by enlargement of the testes and the appearance of pubic hair, followed by the appearance of auxiliary and facial hair. At puberty there is also increased penile length and the onset of spermatogenesis. If signs of puberty are not evident in boys by 14 years of age, a workup for delayed puberty is warranted.

In the prepubertal age group, hypogonadism might be either primary hypogonadism or secondary hypogonadism. To differentiate primary from secondary hypogonadism, early morning luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels must be obtained. Because LH and FSH are secreted during the early morning at the beginning of puberty, it is necessary to measure these hormones in the early morning (8:0010:00 AM). Primary hypogonadism is associated with low levels of testosterone and high-normal to high levels of LH and FSH. Secondary hypogonadism is associated with low levels of testosterone and normal to low levels of LH and FSH.5,6

The signs and symptoms of low testosterone in postpubertal adult males can be more difficult to diagnose and might include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, loss of muscle mass and strength, and some regression of secondary sexual characteristics.13 At the initial visit, the first objective is to distinguish between primary gonadal failure, in which low testosterone is accompanied by increased FSH and increased LH, and hypothalamic-pituitary disorders (secondary hypogonadism), with low testosterone and low to normal FSH and LH levels.

Initial laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone, prolactin, FSH, and LH levels. For the diagnosis of primary hypogonadism, FSH measurement is particularly important because FSH has a longer half life, is more sensitive, and demonstrates less variability than LH.2,3

The aging male patient can present with signs and symptoms of low testosterone, including loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, and loss of muscle mass and strength.13 At the initial visit, laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone. In elderly men, testosterone levels decrease between 15% and 20% over the course of 24 hours.8

Total testosterone levels might be normal with hypogonadism if the SHBG levels are increased.79 Levels of SHBG increase with age, causing a decrease in bioavailable testosterone.9 If testosterone levels are low-normal but the clinical symptoms and signs indicate hypogonadism, measurement of serum total testosterone levels should be repeated and an SHBG level should be determined. With the total testosterone and SHBG levels, a bioavailable testosterone value can be calculated. A bioavailable testosterone calculator is available at http://www.issam.ch/freetesto.htm.

It is usually not necessary to determine FSH or LH levels in the aging male.

It is well accepted that testosterone levels should be measured in the early morning, when they are at their peak level. However, in community practice the choice of which testosterone parameter to measure is still debatable.

Total testosterone assay is widely available and inexpensive to perform. Although the ranges and methods vary, physicians can consult their local laboratories for the applicable values in their clinical practice. Total testosterone values, however, must be interpreted carefully in the aging male because SHBG levels might be elevated. If the total testosterone level is normal in the aging male presenting signs of hypogonadism, the clinician can measure free testosterone or measure SHBG and calculate bioavailable testosterone.9

Free testosterone can be measured by equilibrium dialysis or ultrafiltration, which are difficult to perform and largely unavailable but reliable. In contrast, the radioimmunoassay for free testosterone is widely available but unreliable. Because total testosterone and SHBG assays are readily available and cheap, calculating bioavailable testosterone might be a good compromise. Whichever method is chosen, if the early morning testosterone level is at or below the lower limit of normal for the individual laboratory, then a repeat measurement of the early morning testosterone level should be performed to confirm the result. Because testosterone is secreted in a pulsatile fashion, it is important to obtain 2 early morning testosterone levels.

In selected patients, FSH, LH, and prolactin can be measured. If the FSH and LH levels are raised, this suggests a primary testicular cause, and if levels are low or normal, a hypothalamic or pituitary cause should be considered. A raised prolactin level suggests that further investigation of the pituitary gland should be undertaken.1,2

The clinical signs and symptoms of hypogonadism will vary depending on whether the patient presents before or after puberty. Depending on the age of the patient, the degree of pubertal development is important for establishing the differential diagnosis.

Boys aged 14 years or older should be suspected of being hypogonadal if on examination they have underdeveloped testes, lack of penile enlargement, and absence of pubic, auxiliary, and facial hair.

In patients with primary hypogonadism, history might reveal the cause for primary testicular failure, such as familial autoimmune disease, physical trauma to the testes, or trauma to the testes caused by radiation, chemotherapy, or infection.

A karyotype should be obtained to diagnose chromosomal abnormalities, such as Klinefelters syndrome, and a physical examination will reveal small or absent testes resulting from anorchia, Noonans syndrome, or other testicular disorders.

Hypothalamic or pituitary deficiency might be transitory or permanent. Transient secondary hypogonadism might be related to malnutrition or stress states and can be diagnosed by physical examination and evaluation of the patients growth chart. If permanent hypothalamic or pituitary hormone deficiency is suspected, serum levels of pituitary hormones and magnetic resonance imaging of the brain and pituitary should be obtained to screen for hypothalamic or pituitary disease.

If both physical examination and serum chemistry tests are normal, then by exclusion a diagnosis of constitutional pubertal delay must be considered.

To establish a diagnosis of hypogonadism, it is important to take a careful history to determine whether there have been major medical problems, toxic exposure, concomitant drug therapy that might cause hypogonadism, or fertility problems.

Low libido, impotence, fatigue, impaired concentration, and sexual dysfunction are important clinical problems that might not be raised by the patient in the clinic. Therefore, these symptoms need to be asked about specifically if hypogonadism is suspected.13

Formal assessment of intellectual changes, mood, and cognitive changes can be performed. Changes in lean body mass will be apparent from the medical history and examination, as will changes in hair, skin, and fat distribution. Decreases in bone mineral density might be apparent from a history of recent fractures but can only be confirmed by dual energy x-ray absorptiometry (DEXA).1

Physical examination should include testicular examination, including size and consistency. The distribution and amount of body hair should also be noted. Penile size is not affected by postpubertal testosterone deficiency. An assessment of the prostate by digital rectal examination (DRE) should be performed and a prostate-specific antigen (PSA) value obtained.3

To establish a diagnosis of hypogonadism in the aging male, it is important to assess the patient carefully for signs and symptoms. Low libido, impotence, fatigue, impaired concentration, and sexual dysfunction are important clinical problems that might not be raised by the patient in the clinic, especially by an aging patient. Therefore, as with the younger postpubertal patient, these symptoms need to be asked about specifically if hypogonadism is suspected.1,2 As with the postpubertal patient (see previous section), changes in intellectual functioning; mood; lean body mass; and hair, skin, and fat distribution should all be assessed, and DEXA can be used to confirm decreases in bone mineral density.1

In older patients, an important part of the physical examination includes an assessment of the prostate by DRE and PSA assay. In addition, an assessment of prostate-related symptoms should be undertaken. The presence of gynecomastia or carcinoma of the breast are important physical findings.

In cases of primary and permanent secondary hypogonadism diagnosed in the prepubertal male, life long testosterone treatment is needed. The usual treatment is initiation of therapy with small doses of testosterone (50100 mg IM) every 3 to 4 weeks at the appropriate psychosocial stage in development. When a final adult height is thought to have been obtained, the adult dose of testosterone replacement is inaugurated.

In the postpubertal period, once the diagnosis of testosterone deficiency has been made, replacement therapy should be considered in light of the clinical signs and symptoms in conjunction with the laboratory values. The objective of testosterone replacement therapy is to normalize serum testosterone and maintain the level within the eugonadal state. In addition, treatment objectives might include improving sexual dysfunction, intellectual capacity, depression, and lethargy; maintaining bone mineral density and possibly reducing fracture risk; increasing muscle mass and strength; and enhancing the quality of life.13,9

Although the normal range for serum testosterone might vary between different laboratories, the normal range for early morning testosterone in male adults is approximately 300 ng/dL to 1000 ng/dL.7 An early morning total serum testosterone level of less than 300 ng/dL clearly indicates hypogonadism, and under most circumstances benefit will be derived from testosterone replacement therapy. A healthy male adult patient with a serum testosterone level greater than 400 ng/dL is unlikely to be testosterone deficient, and therefore clinical judgment should be exercised if he has symptoms suggestive of testosterone deficiency.

There are some absolute contraindications to testosterone replacement therapy. These include prostate cancer, which must be assessed by history and clinical examination. If on DRE the prostate is enlarged or if the PSA level is greater than 4.0 ng/mL, biopsy of the prostate should be undertaken to confirm a diagnosis of prostate cancer or benign prostatic hyperplasia (BPH).3

An existing or prior history of breast cancer is also an absolute contraindication to testosterone replacement therapy. Testosterone therapy is known to increase the hematocrit, and therefore a pre-existing hematocrit of 55% or greater is an absolute contraindication to replacement therapy.

Sensitivity to any of the ingredients in the testosterone formulation would also be an absolute contraindication. Relative contraindications include an increased hematocrit, untreated sleep apnea, severe obstructive symptoms of BPH, and advanced congestive cardiac failure.2,3

The goal of replacement therapy is to maintain testosterone in the normal physiological range; therefore, a combination of clinical and biochemical measures should be monitored 6 to 12 weeks after initiating therapy. In most cases, an early morning serum total testosterone level is adequate to determine whether dosage adjustment is necessary. However, patients receiving injections of testosterone enanthate or cypionate every 2 weeks will require an earlier measurement of serum testosterone at 1 to 2 weeks after commencement of therapy.3

Examination of the prostate should be performed routinely, although the exact frequency after initiation of testosterone replacement is still debatable. Digital rectal examination of the prostate and PSA assay should be performed before initiation of therapy, along with an assessment of prostate-related symptoms. In elderly men, a DRE and PSA assay should be performed at 3 and 6 months after commencing testosterone therapy and then annually thereafter.3 A high PSA level should be further evaluated with a highly specific PSA assay, if available. A patient should be referred to a urologist if his PSA level increases over time or if he has a PSA level greater than 4.0 ng/mL.3

It is known that testosterone stimulates bone marrow production of erythrocytes, which might result in an increased hematocrit in some men, and therefore this should be checked at the same time as the PSA level.2,3

Lipid disturbances in testosterone-treated male patients are generally not a problem because the ratio of high-density lipoprotein to total cholesterol usually remains constant. An initial lipid profile should be performed before therapy, and a follow-up profile should be obtained after 6 to 12 months of therapy and annually thereafter.3

Hypogonadism can be of hypothalamic-pituitary origin or of testicular origin, or a combination of both, which is increasingly common in the aging male population. It can be easily diagnosed with measurement of the early morning serum total testosterone level, which should be repeated if the value is low. Follicle-stimulating hormone, LH, and prolactin might also need to be measured. If the clinical signs and symptoms suggest hypogonadism but the serum testosterone level is near normal, then assay of serum testosterone should be repeated in conjunction with SHBG because serum testosterone might be normal in the presence of hypogonadism if the SHBG level is raised, which commonly occurs in elderly male patients.

Before initiation of testosterone replacement therapy, an examination of the prostate, including DRE, PSA assay, and assessment of prostate symptoms should be undertaken, and both the hematocrit and lipid profile should be measured. There are few absolute contraindications to testosterone replacement therapy other than prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation. Monitoring of the prostate (assessed with DRE and PSA assay) and hematocrit and lipid profile should be repeated during testosterone replacement therapy.

The benefits of testosterone replacement therapy may include restoring metabolic parameters to the eugonadal state; improving psychosexual function and intellectual capacity, including depression and lethargy; maintaining bone mineral density and reducing bone fractures; improving muscle mass and strength; and enhancing quality of life.

Hypogonadism is a lack of testosterone in male patients and can be of central (hypothalamic or pituitary) or testicular origin, or a combination of both.

Boys ages 14 years or older should be suspected of being hypogonadal if on examination they have underdeveloped testes, a lack of penile enlargement, and an absence of pubic, auxiliary, and facial hair.

In pre- and postpubertal male patients, primary hypogonadism is associated with low levels of testosterone and high-normal to high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); secondary hypogonadism is associated with low levels of testosterone and normal to low levels of LH and FSH.

In the aging male patient, signs and symptoms of hypogonadism can include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, and loss of muscle mass and strength.

For aging men, laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone; levels less than 300 ng/dL clearly indicate hypogonadism, and under most circumstances benefit will be derived from testosterone replacement therapy.

Before initiation of testosterone replacement therapy, an examination of the prostate and assessment of prostate symptoms should be performed, and both the hematocrit and lipid profile should be measured.

There are few absolute contraindications to testosterone replacement therapy other than prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation.

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Diagnosis of Hypogonadism: Clinical Assessments and Laboratory Tests

Hypogonadotropic hypogonadism (HH) or secondary hypogonadism is defined as a clinical syndrome that results from gonadal failure due to abnormal pituitary gonadotropin levels. HH may result from either absent or inadequate hypothalamic GnRH secretion or failure of pituitary gonadotropin secretion. Several congenital and acquired causes, including functional and organic forms, have been associated with this condition. One important aspect of the HH diagnosis is that it may reflect the presence of a tumor of the hypothalamic pituitary region or even a systemic disease. On the other hand, functional forms of HH, characterized by a transient defect in GnRH secretion, are relatively common in women, in response to significant weight loss, exercise, or stress leading to hypothalamic amenorrhea. HH is typically characterized by low circulating sexual steroids associated with low or inappropriately normal gonadotropin levels. The precise and early diagnosis of HH can prevent negative physical and psychological sequelae, preserve normal peak bone mass, and restore the fertility in affected patients.

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The Endocrine Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Endocrine Society has achieved Accreditation with Commendation.

The Endocrine Society designates this JCEM Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Learning Objectives

Upon completion of this educational activity, participants should be able to:

Recognize the symptoms and signs of hypogonadism throughout different phases of life.

Identify the congenital and acquired causes of hypogonadotropic hypogonadism.

Diagnose hypogonadotropic hypogonadism.

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Authors, editors, and Endocrine Society staff involved in planning this JCEM Journal-based CME activity are required to disclose to The Endocrine Society and to learners any relevant financial relationship(s) of the individual or spouse/partner that have occurred within the last 12 months with any commercial interest(s) whose products or services are discussed in the CME content. The Endocrine Society has reviewed all disclosures and resolved all identified conflicts of interest.

The following authors reported no relevant financial relationships:

Leticia Ferreira Gontijo Silveira, M.D., Ph.D, and Ana Claudia Latronico, M.D., Ph.D., have no relevant financial relationships.

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The Editor-in-Chief, Leonard Wartofsky, M.D., is a Consultant for Asurogen, Genzyme, and IBSA, and is on the Speaker's Bureau for Genzyme. Kenneth Burman, M.D., is a Consultant for Medscape and UpToDate; a Reviewer for the Endocrine Fellows Foundation; and has received Institutional Grants for Research from Amgen, Eisei, and Pfizer. Samuel Dagogo-Jack, M.D., is a Consultant for Merck and Novo Nordisk; a Grantee for the American Diabetes Association, AstraZeneca, Boehringer Ingelheim, National Institutes of Health, and Novo Nordisk; and a Grant Reviewer for the American Diabetes Association and National Institutes of Health. Silvio Inzucchi, M.D., is a Consultant/Advisor for Boehringer Ingelheim, Genentech, Janssen, Merck, and Takeda; has DSMB Activity with Amgen, Esai, and Gilead; and receives CME support from Abbott, Amylin, Boeringher-Ingelheim, Merck, and Takeda. Kieren Mather, M.D., received an Investigator-initiated Grant from Novo Nordisk. Lynnette Nieman, M.D., is an Author/Editor for UpToDate, and receives Research Support from HRA-Pharmaceutical.

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A 19 year-old female, born from nonconsanguineous parents, was referred to the Endocrinology Unit due to primary amenorrhea and poor breast development. Spontaneous partial pubarche and thelarche occurred at 13 and 15 years, respectively. The patient did not report eating disorders or vigorous physical activity. She had no olfactory complaints. She had 2 older brothers with a history of normal pubertal development. At physical examination, she had eunuchoid habitus (height, 155 cm; arm span, 160 cm), weight of 60.7 kg, with normal body mass index of 23 kg/m2. Pubic hair and breast development were Tanner stage II. She had ogival palate and cavus feet, and no other stigmata were observed. Basal hormonal evaluation revealed low serum estradiol (6.8 pg/ml) and suppressed LH (<0.6 IU/L) and FSH (<1.0 IU/L) levels. Upon acute GnRH stimulation test (100 mg iv), peak LH was 1.4 IU/L and peak FSH was 1.7 IU/L. Anterior pituitary function was otherwise normal, including prolactin (9 ng/mL) and thyroid function (TSH, 1.5 IU/L; free T4, 1.1 ng/dL). A formal olfactory test was applied and confirmed normal sense of smell. Her bone age was 13 years. No abnormalities were noticed on abdominal ultrasound examination. Pelvic ultrasound revealed infantile uterus (1.5 cc) and small ovaries (right, 2.6 cc; left, 1.3 cc). Her bone mineral density, corrected for bone age, was reduced, showing osteopenia. Magnetic resonance imaging scan of the hypothalamic-pituitary region was normal.

Pulsatile secretion of GnRH by hypothalamic neurons is a crucial element of the reproductive cascade, initiating the release of pituitary gonadotropins, gonadal secretion of sex steroids, pubertal development, and gametogenesis. Hypogonadotropic hypogonadism (HH) is characterized by failure of gonadal function secondary to deficient gonadotropin secretion (1). This condition is commonly seen in association with other pituitary hormone deficiency states caused by structural lesions of the hypothalamic-pituitary region. However, congenital, acquired, and functional causes have been associated with isolated GnRH deficiency (Tables 1 and 2) (2).

Genes and Their Protein Products Associated With Congenital IHH Phenotype

Genes and Their Protein Products Associated With Congenital IHH Phenotype

Congenital isolated HH (IHH) is characterized by partial or complete lack of pubertal development, secondary to deficient GnRH-induced gonadotropin secretion, in the absence of anatomical abnormalities in the hypothalamic and pituitary region, and normal baseline and reserve testing of the remaining pituitary hormones (1). This genetic condition is classically divided in 2 groups based on the presence or absence of olfaction dysfunction. Around 5060% of the affected individuals exhibit anosmia or hyposmia in association with IHH, defining Kallmann syndrome. Patients with Kallmann syndrome may have additional phenotypic abnormalities including craniofacial defects (cleft lip/palate, high-arched palate, ocular hypertelorism, dental agenesis), neurosensory deafness, digital anomalies (clinodactyly, syndactyly, camptodactyly), unilateral renal agenesis, and neurological defects (oculomotor abnormalities, bimanual synkinesis or mirror hand movements, cerebellar ataxia), whereas normosmic IHH is usually not associated with any other malformations (nonsyndromic condition) (3). In Kallmann syndrome, anosmia is related to hypoplasia or aplasia of the olfactory bulbs, whereas the hypogonadism is due to GnRH deficiency, due to defective migration of olfactory and GnRH neurons. In most vertebrates, the olfactory and GnRH neurons share a common origin in the nasal placode and migrate together across the cribiform plate toward the developing olfactory bulb, explaining the association of HH with olfactory abnormalities (4, 5).

Congenital IHH is a clinically and genetically heterogeneous disorder. Although sporadic cases are the most frequent, families with congenital IHH have been reported with X-linked, autosomal dominant or recessive inheritance. The prevalence of IHH has been estimated at 1/4000 to 1/10 000 males, and it is reported to be 2 to 5 times less frequent in females. The reason for this marked gender discrepancy is not known, and the prevalence of the disease is probably underestimated in females. Male preponderance can be only partially explained by the contribution of men with X-linked disease to the total number of cases (1, 6, 7). Other factors, such as incomplete penetrance, biased referral patterns, with male patients being seen by endocrinologists as opposed to more females being referred and treated by gynecologists, should also be considered.

A growing list of genes has been implicated in the molecular pathogenesis of the congenital IHH, pointing up the heterogeneity and complexity of the genetic basis of this condition (Table 2). These genes encode neuropeptides and proteins involved in the development and migration of GnRH neurons, or in the control of different stages of GnRH function. Mutations in KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1, WDR11, and SEMA3A are associated with defects in neuronal migration, leading to Kallmann syndrome (810). Notably, defects in FGFR1, FGF8, PROKR2, CHD7, and WDR11 have also been associated with normosmic IHH, although in a lower frequency (8, 10). Mutations in KISS1/KISS1R, TAC3/TACR3, and GNRH1/GNRHR, genes that interfere in the secretion and action of GnRH, are described exclusively in patients with normosmic IHH (8, 11). Despite these recent and great advances, the genetic basis of most cases of congenital IHH remains unknown, with the molecular basis of this condition being identified in approximately 30% of patients.

Congenital IHH has been historically defined in traditional Mendelian terms and considered a monogenic disease. However, this concept has been recently reviewed. Pedigrees with great phenotypic variability have been described, and complex genetic transmission (digenic or oligogenic inheritance) has been recently demonstrated (12, 13). Substantial variation in clinical expression of the same genetic defect in families of patients with IHH has been observed, with affected members presenting with Kallmann syndrome, normosmic IHH, isolated anosmia, isolated clefting, simple pubertal delay, or even apparent phenotypic normality, suggesting the possibility that Kallmann syndrome and normosmic IHH may take part of a wider spectrum of disease (3, 10, 13). This variability has been observed mainly in kindreds with mutations in FGF8/FGFR1 and in PROK2/PROKR2 ligand-receptor pairs (3, 13). This type of phenotypic heterogeneity may be ascribed to environmental or epigenetic effects. A second explanation is the coexistence within families of defects in 2 or more different genes that interact functionally, as it has recently been described in a number of families (10, 13).

Acquired causes of HH are mostly due to structural or functional abnormalities involving the hypothalamic-pituitary axis, and most of these patients have multiple pituitary hormone deficiencies. These conditions include infiltrative disorders of the hypothalamic-pituitary tract, such as sarcoidosis, lymphocytic hypophysitis and histiocytosis, space-occupying lesions such as pituitary adenomas, craniopharyngiomas, and other central nervous system tumors (2).

Adult-onset isolated gonadotropin deficiency can be secondary to systemic disorders, drugs, functional abnormalities, or idiopathic. One of the most frequent causes of acquired isolated HH is hyperprolactinemia. Elevated prolactin levels can result mainly from the use of drugs that interfere with the dopaminergic system, lactotroph adenomas (prolactinomas), or from any hypothalamic or pituitary stalk disorder that interrupts hypothalamic inhibition of prolactin secretion. The possibility of nutritional disorders or an undiagnosed chronic illness that may affect the hypothalamic GnRH pulse generator should be evaluated in patients with HH. Hypothyroidism should be ruled out, particularly if growth velocity is below expected and bone age markedly delayed. Hemochromatosis can affect the hypothalamic and pituitary region, leading to progressive isolated gonadotropin deficiency, and should always be ruled out by the presence of normal serum ferritin concentrations. Drugs that can reversibly suppress sex steroid levels include opiates, glucocorticoid, and psychotropic agents such as phenothiazines.

The idiopathic form of adult-onset HH is a rare disorder characterized by an isolated failure of gonadotropin secretion occurring after an otherwise normal sexual maturation in men in whom anatomical, systemic, or functional causes had been ruled out (14). No genetic defect in genes associated with congenital IHH has been identified in this group of patients (15). Long-term follow-up of adult-onset HH individuals revealed that the clinical and hormonal characteristics of these patients did not change over a decade, all of them remaining severely hypogonadal, with testosterone levels below 130 ng/dL, with no spontaneous reversals (15). It is important to differentiate adult-onset HH, characterized by frankly low serum testosterone levels in the presence of low or normal gonadotropins, from the progressive testosterone deficiency observed in a small minority of aging men, known as late-onset hypogonadism. This latter condition has been defined as a syndrome in middle-aged and elderly men reporting sexual symptoms in the presence of moderately low total testosterone levels (<320 ng/dL), with variable levels of gonadotropins, which involves central and mostly gonadal components in its pathogenesis (16, 17).

Functional hypothalamic amenorrhea is a reversible form of GnRH deficiency, usually triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Regardless of the specific trigger, functional hypothalamic amenorrhea is characterized by the suppression of GnRH pulsatility (18). Functional hypothalamic amenorrhea is a frequent cause of acquired female infertility, typically manifested as amenorrhea of 6-month duration or longer, low or normal gonadotropin levels, and hypoestrogenemia without organic abnormalities (19, 20). Interestingly, rare variants in the genes associated with congenital IHH were recently found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to functional changes in GnRH secretion (20). Moreover, the importance of low levels of leptin, a hormone secreted by adipocytes that regulates energy homeostasis, in the pathophysiology of hypothalamic amenorrhea was clearly demonstrated by evidence of a significant improvement of the reproductive and neuroendocrine functions in women with hypothalamic amenorrhea after exogenous recombinant leptin replacement (21, 22). Although primarily a disease of females, eating disorders such as anorexia nervosa are increasingly being recognized in males and are associated with hypogonadism. Population-based studies reported that 515% of all patients with anorexia nervosa are males (23, 24).

Clinical presentation of HH depends on the time of onset (ie, congenital vs acquired), the severity of the defect, and the presence of associated conditions. Typically the diagnosis of congenital IHH is made during the second or third decade of life, when the patients present with delayed pubertal onset, absent or poorly developed secondary sexual characteristics, primary amenorrhea, eunuchoid proportions, or infertility. In some cases, the diagnosis may be suspected before puberty. The occurrence of micropenis and/or unilateral or bilateral cryptorchidism in boys, as well as the presence of other associated congenital abnormalities, such as midline defects, suggests congenital GnRH deficiency, especially in the context of a positive family history (25, 26). In contrast, newborn girls have no obvious abnormal findings that might provide clues to the diagnosis. Most commonly, however, the diagnosis cannot be confirmed until the expected time of puberty onset, except in the neonatal period, when gonadotropin and sexual steroid levels are expected to be elevated. The presence of anosmia is suggestive of Kallmann syndrome, and if the child is too young to undergo olfaction tests, magnetic resonance imaging (MRI) scan showing absent or abnormal olfactory bulbs or sulci strongly suggests the diagnosis. Nevertheless, it is important to note that a normal MRI does not rule out the disease because normal olfactory bulbs can be present in up to 20% of Kallmann syndrome patients (2, 3). Adult-onset HH is characterized in women by secondary amenorrhea, decreased libido, infertility, and osteoporosis; in men, symptoms of decreased libido, lack of morning erection, erectile dysfunction, inability to perform vigorous activity, depression, fatigue, and infertility are observed.

The evidence of low/normal gonadotropin levels in the setting of low concentrations of testosterone in men and estradiol in women indicates the diagnosis of HH. Rarely, selective deficiency of LH or FSH can occur due to inactivating mutations of the specific -subunits (2729). The measurement of morning total testosterone by a reliable assay is strongly recommended in the initial diagnosis test (30). In some men, in whom total testosterone is near the lower limit of normal or in whom SHBG abnormality is suspected, measurement of free or bioavailable testosterone levels is then recommended (23). Anterior pituitary function must be investigated to rule out a more complex endocrine disorder with multiple hormone deficiencies.

Although widely used, the practical value of the GnRH test has been questionable because of its low cost-effectiveness. Indeed, the GnRH test provides no extra diagnostic information relative to baseline gonadotropin levels. In HH patients, the response to GnRH test is highly variable and depends on the severity of the gonadotropin deficiency, which is often reflected by the clinical phenotype. Similarly, the pituitary function can be first evaluated by basal hormonal levels (measured by ultrasensitive assays). Thyroid function should be assessed by TSH combined with free T4. IGF-I can be used to evaluate the somatotropic axis, whereas secondary adrenal deficiency can be assessed by measuring a morning cortisol and ACTH. The stimulatory tests should be reserved for the situations in which the basal hormone measurements are not helpful or if there is strong clinical evidence of a multiple pituitary hormone deficiency.

Anosmia can be easily diagnosed by questioning the patient, whereas olfactometry, such as University of Pennsylvania Smell Identification Test, is necessary to determine reliably whether olfaction is normal or partially defective. Indeed, IHH patients display a broad spectrum of olfactory function, with a significant hyposmic phenotype. Accurate olfactory phenotyping in IHH subjects can inform the pathophysiology of this condition and guide genetic testing (31).

MRI of the hypothalamo-pituitary region is very useful in the management of HH. MRI can demonstrate a malformation, an expansive or infiltrative disorder of the hypothalamo-pituitary region. However, the cost-effectiveness of MRI scan to exclude pituitary and/or hypothalamic tumors is unknown according to the recent clinical practice guideline (30). Pituitary and/or hypothalamic tumors should be investigated by MRI in patients with serum testosterone less than 150 ng/dL, multiple pituitary hormone deficiency, persistent hyperprolactinemia, or symptoms of tumor mass effect (headache, visual impairment, or visual field defect). In the presence of suspected functional causes of HH, such as severe obesity, nutritional disorders, and drugs, MRI is not indicated. Additionally, MRI with specific cuts for evaluating the olfactory tract can be helpful in the diagnosis of Kallmann syndrome. Evidence of unilateral or bilateral hypoplastic/agenesis olfactory bulbs and hypoplastic anterior pituitary is pathognomonic of Kallmann syndrome.

Renal ultrasound examination is usually recommended to patients with syndromic IHH, such as Kallmann syndrome, independent of the genetic basis, although it is well known that unilateral kidney agenesis may be more prevalent in patients with KAL1 defects. The genetic study is usually the last step in the congenital IHH investigation, and complete clinical characterization could certainly help in the gene selection. Bone mineral density of the lumbar spine, femoral neck, and hip is recommended at the initial diagnosis of HH and after 1 to 2 years of sex steroid therapy in hypogonadal patients with osteoporosis or low trauma fracture (30).

The goals of therapy for hypogonadal adolescents or young adults are the induction and maintenance of normal puberty and induction of fertility when the patient desires. testosterone therapy for adult men with symptomatic androgen deficiency is recommended to improve sexual function and sense of well-being and to increase muscle mass and strength and BMD. Testosterone is the primary treatment modality used to induce and maintain secondary sexual characteristics and sexual function in men with HH, but it does not restore fertility.

Intramuscular injections of long-acting testosterone esters (testosterone cypionate or enanthate) are commonly used. In adolescents, the initial dose of testosterone esters to induce puberty is 5075 mg/month, which should be gradually increased every 6 months to 100150 mg/month. The maintenance dose for adult males is 200250 mg im every 23 weeks or 1000 mg of testosterone undecanoate every 3 months. Other options are transdermal preparations, including gel formulations (510 g/d) or 5 mg testosterone patches applied nightly over the nongenital skin (30). The long-term goals of testosterone therapy are to maintain the serum concentrations of sex steroids in the midnormal adult range. Testosterone therapy is not indicated in patients with breast or prostate cancer, a palpable prostate nodule, or indurations, or prostate-specific antigen greater than 4 ng/mL or greater than 3 ng/mL in men at high risk for prostate cancer, hematocrit greater than 50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, or uncontrolled or poorly controlled heart failure (30).

When fertility is desired, gonadotropin therapy is necessary to induce spermatogenesis in males with HH (32). Different treatment protocols can be used in male patients with HH. The typical gonadotropin regimen combines human chorionic gonadotropin (hCG) and FSH. One option is to combine hCG 1000 U and FSH 75 U every other day for HH patients without puberty and immature testes (<3 mL). Notably, the intra-subcutaneous route of administration is as effective as im. The hCG doses should be titrated based on testosterone levels, targeting middle normal values. Testosterone levels usually achieve normal range values by 6 months of continuous treatment in most patients, and spermatogenesis is attained in up to 80% of the cases. Another option for patients with partial pubertal development is to start with hCG alone for 6 months and subsequently add FSH if azoospermia persists. Predictive factors of better outcome include larger testicular volume, absence of cryptorchidism, and higher serum inhibin B levels at the initial medical evaluation.

Treatment of adolescent males with exogenous hCG alone or combined with recombinant FSH for induction of puberty may result in testicular growth and hence improvement in potential fertility compared to treatment with testosterone (32). Early induction of spermatogenesis may reduce the time required for appearance of sperm and the need for prolonged cycles of gonadotropin treatment in adult life. Use of hCG alone appears to be less efficient in spermatogenesis induction and final testicular volume when compared to combined treatment with hCG and FSH (32, 33). Side effects of gonadotropin treatment include the inconvenient way of administration, gynecomastia, and the induction of antibodies to hCG, which can impair the response to hCG in the future (34, 35). It is important to note that there are few studies about the use of gonadotropins in adolescents, and most them are small case series of boys with HH who received pubertal induction with gonadotropins at various times, and thus further studies are needed.

The main and most difficult differential diagnosis of congenital IHH in boys is constitutional delay of growth and puberty. Patients with constitutional delay of puberty typically have delayed growth before puberty and delayed bone age, compatible with the height. In contrast, patients with congenital IHH have normal linear growth during childhood, and despite the absence of the pubertal growth spurt, short stature is not a common finding. The absence of long-bone epiphyseal closure explains the presence of eunuchoid proportions and relative high stature. A variety of physiological and stimulation tests have been proposed, such as LH sampling, prolactin response to various stimulating agents, gonadotropin response to GnRH, testosterone response to hCG, and daily urine excretion of FSH and LH (36). Recently, Coutant et al (37) demonstrated that a single measurement of inhibin B level discriminated IHH from constitutional delay of puberty in adolescent boys. The sensibility and specificity were 100% for inhibin B concentration of 35 pg/mL or less in boys with genital stage 1 (testis volume < 3 mL) in this study (26). Other baseline measurements (anti-Mullerian hormone, testosterone, FSH, and LH) were not useful for such discrimination.

It is notable that men with apparent isolated hypothalamic GnRH deficiency may also have primary pituitary and/or testicular defects (a dual defect) as demonstrated by the atypical responses to long-term exogenous pulsatile GnRH treatment (43). The pituitary and/or testicular defects may be initially masked by the GnRH deficiency in these patients. Therefore, the pathophysiology of hypogonadism in a subgroup of patients with IHH could be more complex than previously thought and possibly not limited to an isolated hypothalamic or pituitary defect.

Interestingly, sustained reversal of hypogonadism has been observed in about 10% of congenital IHH patients after discontinuation of treatment. To date, the triggers leading to reversal of IHH are not well understood. Androgen exposure has been suggested to predispose to reversal, and specific genetic backgrounds are especially prone to reversal HH (38). The reversible form of HH should be suspected if testicular volume increases during testosterone administration or in the absence of endocrine therapy. A brief discontinuation of hormonal therapy to assess reversibility is rational in patients with HH. However, the reversibility may not always be lifelong. Interestingly, heterogeneous genetic background (FGFR1, PROK2, GNRH, CHD7, and TAC/TACR3 mutations) has been associated with reversal of congenital HH (38).

Testosterone replacement in older men is another controversial issue in the practice of medicine. Despite the long existence of testosterone as a pharmaceutical medication, few large-scale, double-blind, placebo-controlled, multiple end point studies had been performed on testosterone therapy in men. In fact, older men are more susceptible to risks from testosterone intervention, such as benign prostatic hyperplasia, prostate cancer, and cardiovascular disease. In addition, many men in the middle to older age group do not fit the simple definition of either primary or secondary hypogonadism but have a mixed type of testosterone deficiency with impairment of both testicular and hypothalamic pituitary signals, indicating that the pathogenesis of low testosterone in this group is not well defined (39, 40).

Low gonadotropin and estradiol levels resulting in primary amenorrhea and poor pubertal development suggested the diagnosis of a severe form of HH in this young lady. The normal remaining pituitary function indicated an isolated form of HH. Her history and physical examination ruled out functional hypothalamic amenorrhea. Central anatomic defects and systemic diseases were excluded by routine tests and a normal brain imaging. The early presentation of the hypogonadism, manifesting as primary amenorrhea, and the association with nonreproductive phenotypes (ogival palate and bone abnormalities) contributed to the hypothesis of a congenital defect in this apparently sporadic case of IHH. Additionally, the normal olfaction test confirmed the diagnosis of idiopathic normosmic IHH. More recently, systematic genetic screening revealed a large heterozygous deletion of FGFR1 in this female with IHH (41).

The case depicted here illustrates the typical clinical presentation of severe female GnRH deficiency. Shaw et al (42) recently demonstrated that the clinical presentation of women with GnRH deficiency can vary from primary amenorrhea and absence of any secondary sexual characteristics to spontaneous breast development and occasional menses. In this large series of women with GnRH deficiency, most patients exhibited some degree of breast development (51%), and a small percentage experienced isolated menses (10%). Hypogonadal women with spontaneous thelarche were more likely to have undergone pubarche, suggesting that aromatization of adrenal androgens could contribute to breast development.

Young women with HH are at risk for bone loss and fracture. Congenital hypogonadism may be particularly detrimental to the skeleton because it may lead to failure to achieve peak bone mass, in addition to loss of established bone mass. Estrogen-progesterone replacement, calcium and vitamin D supplementation, and nutritional counseling should be provided. Multiple formulations of estrogen are available and include oral estradiol, oral conjugated estrogen, transdermal estrogen patches, and gel. In patients who have not yet started pubertal development, estrogen therapy should be started at low doses (5 g ethinyl estradiol, 0.3 mg conjugated equine estrogen, or 0.5 mg micronized estradiol daily) to promote breast development. After 6 months or when breakthrough bleeding occurs, cyclical therapy can be initiated by adding a progestogen, and the dose of estrogen is gradually increased over a 2- to 3-year period. Full replacement dose of estrogen and progesterone is attained with 0.6251.25 mg conjugated equine estrogen daily combined with cyclic 510 mg medroxyprogesterone acetate or 200 mg oral micronized progesterone. Other estrogen options are daily 2 mg micronized estradiol orally, 100200 g transdermal 17-estradiol patches or 12 mg estrogen gel. Alternatively, combined contraceptive pills, usually containing ethinyl estradiol, can be conveniently used. However, natural estrogens are preferable to synthetic estrogens because of incomplete metabolization and a greater risk of thromboembolism and arterial hypertension of the synthetic forms. In patients in whom fertility is desired, induction of gonadotropin secretion by pulsatile GnRH or treatment with exogenous gonadotropin is the current hormonal treatment of choice.

Maestre de San Juan was the first to report, in 1856, the association of the absence of olfactory structures in the brain and the presence of small testes in an individual. Although this description took place more than a century ago, the genetics and natural history of Kallmann syndrome are still incompletely understood. Similarly, testosterone has been available as a pharmaceutical medication since 1930, and it has been used since then to treat failure of male secondary sexual development. Definitely, there are still numerous controversial issues in the practice of medicine, requiring individual good sense for taking decisions regarding whom, when, and how to treat. Long-term and well-controlled studies are necessary to solve the current uncertainties in the field of reproductive disorders.

This work was partially supported by a grant from Conselho Nacional de Desenvolvimento Cientfico e Tecnolgico (CNPq, Productivity in Research, process no. 302825/2011-8; to A.C.L.).

Disclosure Summary: The authors have nothing to declare.

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Continue reading here:
Approach to the Patient With Hypogonadotropic Hypogonadism

Background: Male hypogonadism is a clinical and biochemical androgen insufficiency syndrome, becoming more prevalent with age. Exogenous testosterone is first-choice therapy, with several side effects, including negative feedback of the hypothalamic-pituitary-gonadal axis, resulting in suppression of intratesticular testosterone production and spermatogenesis. To preserve these testicular functions while treating male hypogonadism, clomiphene citrate is used as off-label therapy. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of clomiphene citrate therapy for men with hypogonadism.

Methods: The EMBASE, PubMed, Cochrane databases were searched in May 2021, for effectiveness studies of men with hypogonadism treated with clomiphene citrate. Both intervention and observational studies were included. The Effective Public Health Practice Project Quality Assessment Tool, a validated instrument, was used to assess methodological study quality. The primary outcome measure was the evaluation of serum hormone concentration. Secondary outcomes were symptoms of hypogonadism, metabolic and lipid profile, side effects, safety aspects.

Results: We included 19 studies, comprising four randomized controlled trials and 15 observational studies, resulting in 1642 patients. Seventeen studies were included in the meta-analysis, with a total of 1279 patients. Therapy and follow-up duration varied between one and a half and 52 months. Total testosterone increased with 2.60 (95% CI 1.82-3.38) during clomiphene citrate treatment. An increase was also seen in free testosterone, luteinizing hormone, follicle stimulating hormone, sex hormone-binding globulin and estradiol. Different symptom scoring methods were used in the included studies. The most frequently used instrument was the Androgen Deficiency in Aging Males questionnaire, whose improved during treatment. Reported side effects were only prevalent in less than 10% of the study populations and no serious adverse events were reported.

Conclusion: Clomiphene citrate is an effective therapy for improving both biochemical as well as clinical symptoms of males suffering from hypogonadism. Clomiphene citrate has few reported side effects and good safety aspects.

Keywords: clomiphene citrate; male hypogonadism; testosterone deficiency.

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Clomiphene citrate for men with hypogonadism: a systematic ... - PubMed

What is hypogonadism in females?

Hypogonadism in females describes the inadequate function of the ovaries, with impaired production of germ cells (eggs) and sex hormones (oestrogen and progesterone).

Hypogonadism in females is due to disruption of any section of the hypothalamicpituitaryovarian axis pathway (figure 1). In a correctly functioning hypothalamicpituitaryovarian axis pathway:

Figure 1. The hypothalamicpituitaryovarian axis pathway

Primary ovarian insufficiency and secondary hypogonadism may be congenital or acquired [1,2].

The main mechanism for congenital primary ovarian deficiency remains unknown in the majority of cases. Some cases relate to:

The causes of acquired primary ovarian insufficiency include:

Congenital secondary hypogonadism is gonadotrophin deficiency due to a genetic mutation, such as in Kallmann syndrome.

Acquired secondary hypogonadism can be due to damage to the pituitary/hypothalamus. Causes of acquired secondary hypogonadism can include:

Gonadotropins can be suppressed by:

The clinical features of hypogonadism depend on the age at presentation [3].

Symptoms of low oestrogen levels are rarely present in hypogonadism pre-puberty. The presenting features are absent pubertal development (reduced growth and absence of pubic hair) and primary amenorrhoea (absence of menarche).

After the completion of puberty, the features of hypogonadism include:

The long-term risks of oestrogen deficiency include an increased risk of osteoporosis and cardiovascular disease. The risk is greater with a younger age of onset. In contrast, the risk of breast cancer may be slightly reduced.

Oestrogen has a key role in maintaining skin health. Oestrogen helps maintain skin thickness and collagen levels, skin elasticity, and moisture. It is also thought to play a role in wound healing [4].

Low oestrogen levels are associated with:

Skin changes may also reflect the underlying cause of hypogonadism; for example, hyperpigmentation may be a sign of an autoimmune disease.

If hypogonadism is suspected following a detailed history and examination, the following investigation pathway can be followed.

Treatment of hypogonadism is directed at the underlying pathology where possible, helping the woman become fertile if desired, and preventing the long-term complications of hypoestrogenism (ie, osteoporosis, increased cardiovascular disease, and urogenital atrophy).

As a general rule, women of reproductive age with hypoestrogenism should receive hormone replacement therapy. Specialist input should be sought, as there are potential significant complications of hormone therapy, such as:

Post-menopause, hormone replacement therapy is indicated for significant symptoms.

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Hypogonadism in females | DermNet

Aim: Symptomatic late-onset hypogonadism is associated not only with a decline in serum testosterone, but also with a rise in serum estradiol. These endocrine changes negatively affect libido, sexual function, mood, behavior, lean body mass, and bone density. Currently, the most common treatment is exogenous testosterone therapy. This treatment can be associated with skin irritation, gynecomastia, nipple tenderness, testicular atrophy, and decline in sperm counts. In this study we investigated the efficacy of clomiphene citrate in the treatment of hypogonadism with the objectives of raising endogenous serum testosterone (T) and improving the testosterone/estrogen (T/E) ratio.

Methods: Our cohort consisted of 36 Caucasian men with hypogonadism defined as serum testosterone level less than 300 ng/dL. Each patient was treated with a daily dose of 25 mg clomiphene citrate and followed prospectively. Analysis of baseline and follow-up serum levels of testosterone and estradiol levels were performed.

Results: The mean age was 39 years, and the mean pretreatment testosterone and estrogen levels were 247.6 +/- 39.8 ng/dL and 32.3 +/- 10.9, respectively. By the first follow-up visit (4-6 weeks), the mean testosterone level rose to 610.0 +/- 178.6 ng/dL (P < 0.00001). Moreover, the T/E ratio improved from 8.7 to 14.2 (P < 0.001). There were no side effects reported by the patients.

Conclusions: Low dose clomiphene citrate is effective in elevating serum testosterone levels and improving the testosterone/estradiol ratio in men with hypogonadism. This therapy represents an alternative to testosterone therapy by stimulating the endogenous androgen production pathway.

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Clomiphene citrate effects on testosterone/estrogen ratio in male ...

With the intensified direct-to-consumer marketing of male sexual medicine treatments, the recent legislative changes in reproductive rights and their unknown long-term effect on assisted reproduction availability for infertile men, and the explosion of telehealth, the practice of male sexual medicine is evolving at a breakneck pace. Specialists in male sexual and reproductive medicine have been tasked with digesting the evolving literature and forming evidence-based treatment guidelines for men with erectile dysfunction, Peyronie disease, infertility, and a host of other conditions. Compared with other areas of urology and medicine in general, male sexual and reproductive medicine has a disappointingly small number of well-designed prospective studies, along with a significant gap in funding for male reproductive health compared with female reproductive health. Several manuscripts published in 2022 started to narrow this gap and provide valuable level 1 evidence supporting (or discounting) key areas within sexual medicine and infertility.

For men with severe male factor infertility and nonobstructive azoospermia, surgical intervention is often indicated to retrieve sperm. Testicular sperm aspiration (TESA) and microdissection testicular sperm extraction (mTESE) are 2 commonly used approaches. A recent study by Jensen et al compared the efficacy of these 2 approaches in one of the few prospective randomized-controlled trials in male infertility.1 In the study, 49 patients were randomly assigned to mTESE with a sperm retrieval rate of 43%, and 51 patients were randomly assigned to TESA with a sperm retrieval rate of 22%. Men with failed TESA then went on to salvage mTESE with a combined sperm retrieval rate of 29%. Participants in the mTESE arm, however, had decreased postoperative testosterone levels, and 24% of participants experienced de novo hypogonadism at 6 months. Prior literature has suggested the testosterone drop is transient and that it will likely recover by 12 months. In summary, the study results showed that mTESE remains the gold standard for treatment of nonobstructive azoospermia, but patients should be counseled on the risk of de novo hypogonadism.

Despite this, mTESE success rates remain modest and are subject to the expertise and skill level of the laboratory and andrologist processing the tissue. Multiple hours can be spent trying to find the few viable sperm hidden among a sea of distractors. A recent study by Lee et al examined the power of artificial intelligence to detect human sperm in semen and mTESE samples using bright-field microscopy for nonobstructive azoospermic (NOA) patients.2 They first trained the program to identify sperm from semen samples of fertile patients. After validating the effectiveness of their algorithm, they retrained it to identify sperm in tissue from NOA patients that had been spiked with large amounts of sperm. When testing it on samples containing 3000 to 6000 sperm among other cell types, they achieved 84.0% positive predictive value and 72.7% sensitivity. Finally, without retraining their algorithm, they tested it on samples containing 10 to 200 sperm, replicating the rare sperm phenomenon seen in patients with NOA. Their model was able to detect 2969 sperm cells out of a total 3517 with an 84.4% PPV and 86.1% sensitivity. The clinical applications of artificial intelligence and machine learning in medicine continue to expand and have made their way to male infertility. Although this is not ready for immediate clinical use, it does highlight the need for further work to harness the power of technology to improve workflow of andrologists and in turn increase the success of infertility care for patients.

There has been a rapid rise in the need for male sexual health and reproductive specialists as the population ages and the number of comorbidities rise, although certain disease processes that fall within this specialty may be able to be addressed by a general urologist. In an analysis of the current educational landscape, Asanad et al call attention to the need for a structured educational curriculum in residency for male infertility.3 In a survey of urology residents, 54 of 72 respondents (75%) reported that male infertility comprises less than 10% of their training. Compared with residents who did not learn from infertility-trained faculty, residents who were exposed to infertility-trained faculty were 14.4 times more likely to feel confident performing infertility procedures (P < .001) and were more likely to feel confident performing fertility procedures after residency (P = .001).3 For trainees, their career depends on what they are exposed to. Smaller subdisciplines within urology may be more difficult to teach uniformly, and perhaps there are ways to improve the exposure to these areas for motivated residents (eg, visiting other programs).

Within male sexual health, one disease process that all urologists should be able to diagnose and initially manage is erectile dysfunction (ED). With studies citing the prevalence of ED as high as 52%, the demand for providers to manage ED remains sky high. Current treatment options include phosphodiesterase type 5 inhibitors (PDE5is), intracavernosal injections, vacuum erection devices, and penile prosthesis. A newcomer to the field is shock wave therapy, which uses controlled energy to induce angiogenesis.

The short-term effectiveness of focused shock wave therapy for patients with moderate ED was investigated in a double-blind, randomized, sham-controlled trial.4 In this study of 70 patients with moderate ED, 35 were randomly assigned to low-intensity shock wave therapy (LiST) and the other 35 were randomly assigned to sham therapy. After a 4 week washout from PDE5i, patients underwent LiST or sham twice weekly for 6 weeks. One month after treatment completion, 59% patients in the LiST group experienced an International Index of Erectile Function (IIEF) score improvement of at least 5 points, compared with 1 patient (2.9%) in the sham group (P < .001). This effect remained present at 3 months post treatment. Thus, the short-term data for LiST are compelling and suggest this may be a viable option in the management of vasculogenic ED for men with mild/moderate ED. Further studies are desperately needed to validate these findings, and urologists have an obligation to provide patients with an honest assessment of the data and only recommend treatments where the risks (including the financial burden) are outweighed by the benefits.

In stark contrast to focused therapy, radial shock wave therapy uses low-pressure radial shock waves to treat ED. In order to characterize its effectiveness, a randomized, double-blind, sham-controlled clinical trial enrolled 80 men with mild to moderate ED.5 Patients were treated weekly with either radial wave therapy or sham therapy for 6 weeks, and the primary outcome measured was change in the IIEF score between baseline and after treatment. Study results showed that there was no significant difference in IIEF scores between groups at 6 weeks or 10 weeks after randomization. Study results displayed the lack of evidence to support the use of radial wave therapy.

Despite the evidence of their ineffectiveness in managing ED, shock wave therapy and particularly radial wave therapy have been heavily marketed directly to consumers in the US. A recent article using a secret-shopper method found troubling marketing and practice trends in the US. The authors noted that patients often are not adequately educated on the different types of treatments and may not know if the administrator is a licensed medical professional.6 With the average cost of treatment ranging from $2600 to $3900 per cycle, clinics offering radial wave therapy have an obvious financial incentive to continue marketing despite the lack of evidence of its effectiveness.

Recent advancements in the field of male sexual health and reproduction present a bright future for the field with new diagnostic and therapeutic options on the horizon. However, it is apparent that demand still outpaces supply for mens health specialty care. Urologists must work diligently to fill this void to not only increase access for patients to receive evidence-based care, but also to prevent men from falling to prey to practices looking to take advantage of this unmet demand and a vulnerable patient population.

References

1. Jensen CFS, Ohl DA, Fode M, et al. Microdissection testicular sperm extraction versus multiple needle-pass percutaneous testicular sperm aspiration in men with nonobstructive azoospermia: a randomized clinical trial. Eur Urol. Published online May 19, 2022. doi:10.1016/j.eururo.2022.04.030

2. Lee R, Witherspoon L, Robinson M, et al. Automated rare sperm identification from low-magnification microscopy images of dissociated microsurgical testicular sperm extraction samples using deep learning. Fertil Steril. 2022;118(1):90-99. doi:10.1016/j.fertnstert.2022.03.011

3. Asanad K, Nusbaum D, Fuchs G, Rodman JCS, Samplaski MK. The impact of male infertility faculty on urology residency training. Andrologia. 2022;54(8):e14457. doi:10.1111/and.14457

4. Kalyvianakis D, Mykoniatis I, Pyrgidis N, et al. The effect of low-intensity shock wave therapy on moderate erectile dysfunction: a double-blind, randomized, sham-controlled clinical trial. J Urol. 2022;208(2):388-395. doi:10.1097/JU.0000000000002684

5. Sandoval-Salinas C, Saffon JP, Martnez JM, Corredor HA, Gallego A. Are radial pressure waves effective for the treatment of moderate or mild to moderate erectile dysfunction? A randomized sham therapy controlled clinical trial. J Sex Med. 2022;19(5):738-744. doi:10.1016/j.jsxm.2022.02.010

6. Weinberger JM, Shahinyan GK, Yang SC, et al. Shock wave therapy for erectile dysfunction: marketing and practice trends in major metropolitan areas in the United States. Urol Pract. 2022;9(3):212-219. doi:10.1097/UPJ.0000000000000299

Read more from the original source:
Male sexual health and reproductive medicine: All that glitters is not gold - Urology Times

NEW YORK, Sept. 19, 2022 /PRNewswire/ --The male hypogonadism market has been segmented by type (Klinefelter syndrome, Kallmann syndrome, and pituitary disorders) and geography (North America, Europe, Asia, and Rest of World (ROW)). North America will account for 37% of the market's growth during the forecast period. This growth is attributed to factors such as the significant increase in the prevalence of male hypogonadism. Moreover, market growth in this region will be faster than the growth of the market in other regions. The US and Canada are the key countries for the male hypogonadism market in North America.

Themale hypogonadism market size is estimated to grow by USD 684.95 mn from 2021 to 2026. In addition, the growth momentum of the market will accelerate at a CAGR of 5.09% during the forecast period.

Technavio provides a comprehensive report summary describing the market size and forecast along with research methodology. The FREE sample reportis available in PDF format

Company Profiles

The male hypogonadism market report includes information on the product launches, sustainability, and prospects of leading vendors, including AbbVie Inc., Aytu BioPharma Inc., Bayer AG, Bio Techne Corp., Diurnal Group Plc, Eli Lilly and Co., Endo International Plc, Ferring B.V., IBSA Institute Biochimique SA, Lipocine Inc., Merck and Co. Inc., Perrigo Co. Plc, Pfizer Inc., and Teva Pharmaceutical Industries Ltd. The key offerings of some of these vendors are listed below:

Technavio's reports provide key strategic initiatives used by vendors, along with key news and the latest developments. View our FREE PDF Sample Report Now

Competitive Analysis

The competitive scenario provided in the male hypogonadism market report analyzes, evaluates, and positions companies based on various performance indicators. Some of the factors considered for this analysis include the financial performance of companies over the past few years, growth strategies, product innovations, new product launches, investments, growth in market share, etc.

Market Dynamics

Factors such as an increase in the incidence of hypogonadism and the increasing awareness about male hypogonadism and its treatment options will be crucial in driving the growth of the market. However, the loss of patent exclusivities and increasing generic competition will restrict the market growth.

Technavio has identified key trends, drivers, and challenges in the market, which will help vendors improve their strategies to stay ahead of their competitors. View our FREE PDF Sample Report

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Male Hypogonadism Market Scope

Report Coverage

Details

Page number

120

Base year

2021

Forecast period

2022-2026

Growth momentum & CAGR

Accelerate at a CAGR of 5.09%

Market growth 2022-2026

USD 684.95 million

Market structure

Fragmented

YoY growth (%)

3.52

Regional analysis

North America, Europe, Asia, and Rest of World (ROW)

Performing market contribution

North America at 37%

Key consumer countries

US, Canada, Germany, UK, and China

Competitive landscape

Leading companies, competitive strategies, consumer engagement scope

Companies profiled

AbbVie Inc., Aytu BioPharma Inc., Bayer AG, Bio Techne Corp., Diurnal Group Plc, Eli Lilly and Co., Endo International Plc, Ferring B.V., IBSA Institute Biochimique SA, Lipocine Inc., Merck and Co. Inc., Perrigo Co. Plc, Pfizer Inc., and Teva Pharmaceutical Industries Ltd.

Market Dynamics

Parent market analysis, market growth inducers and obstacles, fast-growing and slow-growing segment analysis, COVID-19 impact and future consumer dynamics, and market condition analysis for the forecast period.

Customization purview

If our report has not included the data that you are looking for, you can reach out to our analysts and get segments customized.

Browse Health CareMarket Reports

Table of Contents

1 Executive Summary

2 Market Landscape

3 Market Sizing

4 Five Forces Analysis

5 Market Segmentation by Type

6 Customer Landscape

7 Geographic Landscape

8 Drivers, Challenges, and Trends

9 Vendor Landscape

10 Vendor Analysis

11 Appendix

About Us

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Male Hypogonadism Market Size to Grow by USD 684.95 Mn, AbbVie Inc. and Bayer AG Among Key Vendors - Technavio - Longview News-Journal

For a study, researchers sought to assess the reproductive success of hypogonadotropic hypogonadism (HH) patients who underwent in vitro fertilization and embryo transfer (IVF-ET).

From 2010 to 2019, the Center for Reproductive Medicine at Peking University Third Hospital analyzed retrospectively the reproductive outcomes of 81 HH patients and 112 controls who had oocyte retrieval.

The HH group had significantly lower baseline levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), androstenedione (A), and prolactin (PRL) than the control group. The total number of oocytes retrieved, the number of fertilized embryos, the number of 2 pronuclear (2PN) embryos, transferable embryos, fertilization rates, and the number of 2PN rates were comparable between the 2 groups, despite the HH patients needing a significantly longer stimulation and higher gonadotropin (Gn) doses than the control patients. Although the control groups live birth rate (LBR) was greater than the HH groups during the first fresh cycle, there was no statistically significant difference. Then, HH patients were further separated into 2 categories based on the cause. Congenital HH (CHH) was diagnosed in 41 instances, while acquired HH (AHH), which includes pituitary HH (PHH), was diagnosed in the remaining 40 cases. According to the findings, there were no appreciable variations between the two groups in terms of fundamental clinical traits and IVF parameters. About 119 oocyte retrieval cycles were completed in the HH group, and they reacted suitably to ovulation induction. In 90 cycles, urinary human menopausal gonadotropin (HMG) was administered alone; in the remaining 29 cycles, HMG and recombinant human follicle stimulating hormone (rFSH) were combined. IVF-related factors did not significantly differ between the 2 groups. After the first, second, and more or less than third cycles, the conservative cumulative live birth rates (CLBRs) were 43.21%, 58.02%, and 60.49%, respectively, whereas the corresponding optimum CLBRs were 43.21%, 68.45%, and 74.19%. Preterm birth (PTB) rates were 8.33% (3/36) and 30.77% (4/13) for singletons and twins, respectively, in HH patients.

IVF-ET is a successful therapy for infertility in HH patients, and patients can experience satisfying pregnancy results.

Reference: frontiersin.org/articles/10.3389/fendo.2022.850126/full

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The Reproductive Outcome of Women with HH in IVF - Physician's Weekly

New Jersey, United States Analysis of Mens Health Market 2022 to 2028, Size, Share, and Trends by Type, Component, Application, Opportunities, Growth Rate, and Regional Forecast

From the name itself, obviously mens health refers to an operation that involves providing therapeutics, drugs, precautionary measures against diseases and infections and surgical offerings to the male population of patients. Mens health is worried about improving the general health of male population. Improving the general nature of healthcare services is an important drive. Providing the best healthcare services ensures better management of diseases and disorders. Male population also suffers numerous problems most of which they are shy of discussing. Yet, with the rising awareness about personal health, the market is set to fill from here on out. IBI analyses that the mens health market is expected to go through a CAGR of 15.00% during the forecast period. Hospitals overwhelm the end use segment of the mens health market attributable to the developing number of hospitals especially in the developing economies.

The Mens Health market, which was valued at US$ million in 2022, is expected to grow at a CAGR of approximately percent over the forecast period, according to our most recent report.

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Developing frequency pace of several male conditions universally is one of the central points fostering the development of the market. Increasing frequency of hypogonadism therapy, prostate disease therapy, erectile dysfunction therapy, premature discharge therapy and others is straightforwardly propelling the market development rate. Rising expenditure for research and development proficiencies especially in the developed and developing economies pertaining to the clinical instruments and devices will additionally set out worthwhile market development open doors. Research and development proficiencies being led for the advancements in clinical technologies and devices is also bolstering the market development rate. Surging focus towards improving the state of healthcare facilities and improving the general healthcare infrastructure is another important variable fostering the development of the market. Rising number of partnerships and strategic collaborations between the public and private players pertaining to subsidizing and application of better than ever innovation is further setting out worthwhile market open doors.

The COVID-19 pandemic essentially impacted the market. This is because of the way that most of the healthcare resources were coordinated towards fulfilling the need arising out of COVID-19 patients. Postponement of non-elective surgeries and unnecessary healthcare procedures has additionally wrecked the market development rate in this pandemic period. Further, restrictions imposed on making a trip inferable from the lockdown regulations further tested the market development rate in this period. In any case, the post pandemic period will help to produce profits and revenues. Also, absence of ideal reimbursement scenario and innovation penetration in the developing economies, significant expenses associated with the procedure, restricted insurance inclusion and administrative compliance, and absence of suitable infrastructure in low-and center pay countries are projected to challenge the market in the forecast period of 2022-2028.

Division Segment

The mens health market is segmented on the basis of application and end use. The development amongst these segments will help you examine small development segments in the industries and provide the users with a significant market outline and market insights to help them pursue strategic choices for distinguishing center market applications. Based on product, the mens health market is segmented into male hypogonadism therapy, prostate malignant growth therapy, erectile dysfunction therapy, premature discharge therapy and others. Mens health market has also been segmented based on the end use into hospitals, diagnostic centers, clinics and others.

Regional Analysis

The nation section of the report also provides individual market impacting factors and changes in guidelines in the market domestically that impacts the current and future trends of the market. North America dominates the mens health market because of the strong base of healthcare facilities, widespread usage of medications, increasing consciousness with respect to the essence of keeping up with great health and rising number of research activities around here.

Asia-Pacific is expected to witness significant development during the forecast period of 2022 to 2028 because of the increase in government initiatives to promote awareness, rise in clinical tourism, developing research activities in the locale, accessibility of massive untapped markets, increasing of the incidences of osteoarthritis, fruitlessness, and different disorders huge population pool, and the developing interest for quality healthcare in the area.

Competitive Analysis

The mens health market competitive landscape provides details by competitor. Details included are company outline, company financials, income created, market potential, investment in research and development, new market initiatives, worldwide presence, production sites and facilities, production capacities, company strengths and weaknesses, product send off, product width and expansiveness, application predominance. The above information points provided are simply connected with the companies focus connected with the mens health market.

Some of the central parts operating in the mens health market are:

Novartis AG (Switzerland)Pfizer Inc. (US)Merck & Co., Inc. (Germany)Novo Nordisk A/S (Denmark)Amgen Inc. (US)Lupin Pharmaceuticals, Inc. (India)AstraZeneca (UK)F. Hoffmann-La Roche Ltd (Switzerland)Sanofi (France)Johnson & Johnson Services, Inc. (US)GlaxoSmithKline plc (UK)Bayer AG (Germany)Bristol-Myers Squibb Company (US)

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Men's Health Market is Slated to Witness Tremendous Growth in Coming Years | Latest Report by IBI - Digital Journal

To find out whether a patient may be at risk of osteoporosis, there is a mechanism that allows for screening: bone densitometry.

Rheumatologists indicate that in osteoporosis, in addition to the loss of mass, the microscopic architecture of the bone is affected. Photo: Shutterstock.

Within the framework of Reuma Expo 2022, experts warn that a variety of Medicine Focusing on getting relief from illnesses or other types of conditions in the body that can have an impact on the development of osteoporosis, In this regard, Dr. Noemi Varela Rosario and Dr. Ramn Ortega Coln, board members of the Puerto Rican Foundation for Rheumatic Diseases, called on patients to consult with their doctors about the effects and risks of certain medications.

In osteoporosis bone resorption occurs, so mass is lost he is And the body is unable to repair it in the same way. In addition to this loss of mass, the bone microarchitecture is affected, which gradually weakens the structure, producing brittleness and potential future fractures in patients.

Dr. Noemi said, We usually see patients who have back pain and buy medication or some who constantly take antacids like omeprazole and pantoprazole without realizing that it may add other risks.

In that sense, Dr. Ortega explained that when we Medicine By which the acid in the stomach dries up, we can create an atrophy of the gastric mucosa and prevent the absorption of minerals that the bone needs, creating a greater risk osteoporosis,

Regarding this condition, rheumatologists also indicated that, as in the case of vertebrae, fractures may be silent, with the patient losing the vertebral mass as well as its height, in addition to falling over the years.

According to the Spanish Foundation of Rheumatology, the drug best known for its effects on bone is glucocorticoid, but many bone metabolisms can also be altered. Medicine,

Various studies indicate that osteoporosis Another major cause of this is glucocorticoid-induced osteoporosisPostmenopausal, and its first cause osteoporosis Secondary. It is also considered a model of osteoporosis drug induced.

It is noteworthy that vertebral fractures are the most frequent consequence of chronic glucocorticoid administration, however, the intensity of the loss of mineral density he is It depends on the daily dose, timing of administration and cumulative dose.

However, according to the Rheumatology Foundation, the following Medicine May also play a role in the development of this condition: L-thyroxine, heparin, antiepileptics, neuroleptics, chemotherapy, aromatase inhibitors, GnRH, methotrexate, cyclosporine A, proton pump inhibitors, antidepressants: tricyclic and selective inhibitors of serotonin, lithium, loop. diuretics, and thiazolidinediones.

In the case of cancer patients, the risk of suffering osteoporosis This is more due to the effects of chemotherapy, radiotherapy, hormonal treatments and non-hormonal treatments.

Gonadotropin-releasing hormone (GnRH) analogs have an antigonadotropic effect in men and women. They are used for the treatment of prostate cancer and endometriosis and have a rapid increase in resorption after 6-12 months of treatment. he isMainly trabecular bone loss and increased risk of fracture.

The American Society of Oncology recommends that fracture risk assessment and dual-source X-ray densitometry be performed on all patients with hypogonadism or starting treatment with aromatase inhibitors.

Screening Test: Bone Densitometry

To find out if a patient may be at risk of osteoporosis or even suffer from it, rheumatologists have a mechanism that allows screening and seeing how fragile it is; Densitometry is he is,

In this regard, Dr. Ortega explained that this test is usually done around menopause in the case of women, because estrogens keep bone healthy and strong, but they decrease and estrogen is needed to maintain health. is important. he is,

He also indicated that densitometry he is This is a simple way to measure bone mass in the vertebrae and hip, in the neck of the femur, and in the total area of the hip.

Once the patient learns he has a mass, he is given a follow-up he is Less, it is a preventive treatment on a case by case basis. There are reasons where the patient may have osteoporosis Because she has certain diseases since childhood that weaken her bones, who have intestinal inflammation, who has malnutrition, who has alcohol, who smokes or is extremely thin. Different causes should be investigated in each patient who develops osteoporosisEmphasised the rheumatologist.

After Densitometry Test he isThe expert indicated that there are certain parameters established by the World Health Organization to provide preventive treatment to the patient, according to their risk factors, whether they are lifestyle habits or family history.

We have many ways to deliver preventive treatment. There are Medicine which prevents the loss of mass he isand these are Medicine Most commonly used: alendronate and risedronate. there are Medicine that if we look at a relatively young patient who has lost mass he isStimulates bone formation and helps the patient with A. must be used early to prevent brittleness Quite serious he added.

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Why Can Some Medicines Increase The Risk Of Osteoporosis? - Nation World News

Short facts about Erectile dysfunction (aka ED)

Erectile dysfunction (ED) means the continued inability to attain and keep an erection sufficient to allow satisfactory sexual execution. Erectile dysfunction has a substantial impact on the material and psychological fitness of men worldwide and can also impact the quality of life of both the sufferers and their members.

Penile erection is a complicated phenomenon which affects a delicate and coordinated harmony between neurological, vascular and tissue boxes. This has arterial dilation, relaxation of the trabecular soft muscle, and activation of the human VENO-occlusive tool.

The multiple common danger factors for erectile dysfunction have cardiovascular disease, hypertension, diabetes mellitus, hyperlipidaemia, hypogonadism, lower urinary tract signs, and smoking.

Erectile dysfunction signs may seem to most guys as transient, but in fact, the symptomatology is ongoing. It can generate a lot of negativity if not dined.

Experts in sexual medicine report the reality that most cases that confront erectile dysfunction (ED) dont recognise the extent of the disease and tend to forget it.

Penile erection is a spinal reflex that is triggered by autonomic and bodily penile afferents and by supraspinal results from visual, olfactory, and imaginary incentives. There are many central transmitters interested in erectile power, some of them with a facilitatory function and others with an inhibitory function.

The central transmitters with a facilitatory function in the penile erection are:

The degree of compaction of the soft muscle cells in the corpus cavernosal is determined by the ratio between contracting and relaxant factors. Noradrenaline arrangements both smooth muscles of the corpus cavernosum and penile vessels via the push of 1-adrenoceptors, while nitric oxide is believed the most significant element for relaxation of penile vessels and corpus cavernosum.

Nitric oxide is removed during sexual motivation. It starts the enzyme called guanylate cyclase, resulting in an improved status of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. This, in turn, results in soft muscle relaxation, permitting an increased inflow of blood into the penis. The class of cyclic guanosine monophosphate is controlled by the rate of synthesis via guanylate cyclase and by the speed of degradation via cyclic guanosine monophosphate hydrolysing phosphodiesterase (aka PDEs).

Issues with blood flow, nerve stores or hormones can affect regular erectile function. One of the conditions that cause blood flow issues is atherosclerosis. In patients with atherosclerosis, the arteries in the penis are limited and blocked, preventing the required blood flow to the penis to have an erection.

The most typical physical or organic reasons for erectile dysfunction are:

Patients who are carrying drugs and mourning from erectile dysfunction should confer with their healthcare skills to see if any of the drugs may be a cause of the issue. These drugs have also illicit and/or recreational drugs. Drugs and drugs that cause erectile dysfunction or other sexual issues as side consequences are typically named for men without them understanding the dangers.

Drugs that could be interested in the event of erectile dysfunction are:

Selective phosphodiesterase type 5 inhibitors (aka PDE5Is) describe the first line of therapy for erectile dysfunction These drugs are highly efficacious, are well tolerated, and have very good safety shapes. Four phosphodiesterase kind 5 inhibitors are open on market: sildenafil, vardenafil, tadalafil and avanafil. These agencies do not instantly cause penile erections but rather affect the reaction to sexual stimulation.

Sildenafil was the foremost in this series of phosphodiesterase type 5 inhibitors. As per the European policies the choice between a short-acting phosphodiesterase type 5 inhibitor and a long-acting phosphodiesterase type 5 inhibitor relies on the commonness of intercourse (less use or regular therapy, 2-4 times weekly) and the patients unique background.

Other medications for erectile dysfunction have:

Kamagra is also one of the best alternatives to Viagra, due to being less expensive and it works the same as Viagra and that is why people always tend tobuy Kamagra.

Q1- What other therapies are available for erectile dysfunction? Can I dine my erectile dysfunction without drugs?

Lifestyle changes:

DISCLAIMER:

We may receive commissions and other revenues from this article. We are a paid partner of organizations mentioned in this article.

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The endocrine system isn't talked about often and many people have never heard of it, but we rely on it for several vital functions that affect our mood, growth, metabolism, development and sexual health. The endocrine system includes eight major glands and when hormone levels are too high or low, your overall well-being can be greatly affected. Eat This, Not That! Health spoke with Kanchana Viswanathan, M.D, FACE with Dignity Health St. Mary who shares what to know about the endocrine system and symptoms to pay attention to that indicate you could have a disorder. As always, please consult your physician for medical advice. Read onand to ensure your health and the health of others, don't miss these Sure Signs You've Already Had COVID.

Dr. Viswanathan tells us, "Endocrine System comprises multiple hormone producing glands secreting a variety of hormones -like Insulin (yes -insulin is a hormone ) secreted from pancreas, thyroid hormone from thyroid gland , steroid hormones like cortisol from adrenal gland sex hormones -estrogen, testosterone from ovaries and testicles. There are also major hormone producing glands like the pituitary and parathyroid glands. These hormones have effects on multiple cells throughout the body. Hence any dysfunction of the endocrine system causes symptoms affecting the entire body."

Dr. Viswanathan says, "Common signs of endocrine imbalance include: "Fatigue, unintentional weight loss or weight gain,blood pressure changes , changes in heart rhythm, irregular periods in women, infertility, erectile dysfunction and infertility in men."

According to Dr. Viswanathan, "Endocrine hormones like insulin and thyroid hormone affect multiple levels of metabolism. Insulin is an essential hormone to metabolize carbohydrates and provide the energy for cellular activities and storage of food for later use. Insulin secretion abnormalities lead to diabetes and signs of diabetes can be fatigue, weight loss, excessive thirst and urination."

Dr. Viswanathan explains, "Thyroid hormone deficiency (Hypothyroidism) can slow down metabolism and cause weight gain. Thyroid hormone also affects heart rhythm and heart muscle function."

Dr. Viswanathan shares, "Excess thyroid hormone (Hyperthyroidism) can increase heart rate. A hyperthyroid state can cause arrythmias (abnormal heart rhythm) including atrial fibrillation."6254a4d1642c605c54bf1cab17d50f1e

Dr. Viswanathan says, "Adrenal gland makes steroids like cortisol which is a stress hormone and a deficiency of cortisol (Adrenal Insufficiency) will lead to excessive fatigue , weight loss and low blood pressure. Excess cortisol (Cushing's) causes fatigue along with weight gain, high blood pressure and high blood sugar (diabetes).

Dr. Viswanathan states, "Sex steroids (Estrogen) disorder in women can lead to irregular cycles, infertility. A common ovarian hormonal disorder is PCOS (Polycystic Ovarian Syndrome).

"Low testosterone in men (Hypogonadism ) causes fatigue, erectile dysfunction and decrease in muscle mass," Dr. Viswanathan says.

Dr. Viswanathan advises, "If one experiences any of the symptoms -best option is to see your primary care physician for the appropriate lab work. Many of the hormone disorders like diabetes and thyroid can be confirmed with simple lab tests. Based on the physical exam and labs the physician can initiate treatment and if needed refer to an endocrinologist."

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Sure Signs Your Endocrine System Isn't as Strong as it Should Be Eat This Not That - Eat This, Not That

Aaron Rodgers revealed last week that during a trip to South America he consumed the plant-based psychedelic drug ayahuasca, and that it helped him to improve his performances for the Green Bay Packers.

A number of figures associated with the NFL expected the league to punish Rodgers, but that will not happen.

NFL spokesman Brian McCarthy told the Milwaukee Journal Sentinel that finding any trace of the substance in Rodgers system would not have meant a positive result under the NFLs drug abuse policies.

The NFL and the NFL Players Association established a list of prohibited substances in the last collective bargaining agreement, but ayahuasca is not on it, so the Packers quarterback did not break any rules.

On the list of 191 prohibited substances agreed upon by the players union and the league, synthetic cannabinoids are prohibited by the league, but not ayahuasca. Drugs on the banned list are separated into anabolic agents, masking agents and stimulants. Among the best known prohibited substances are growth hormones, clenbuterol, methyltestosterone, nandrolone and stimulants such as Adderall and Ritalin.

Players may receive a therapeutic use exemption from the league through an independent administrator, to treat hypertension, hypogonadism, hypopituitarism, baldness and attention deficit hyperactivity disorder.

Read more:
What has the NFL said about Packers QB Rodgers consuming ayahuasca? - AS USA

Male hypogonadism, also known as testosterone deficiency, is a failure of the testes to produce the male sex hormone testosterone, sperm, or both.

It can be due to a testicular disorder or the result of a disease process involving the hypothalamus and pituitary gland.

Hypogonadism can affect many organ functions and it can have a negative impact on quality of life.

The signs and symptoms depend on when it starts, how severe the deficiency is, and whether or not there is a decrease in the major functions of the testes.

A lack of testosterone can cause a wide range of symptoms.

These depend on:

Adolescents and young adults who have not yet completed puberty appear younger than their chronological age.

They may also have small genitalia, a lack of facial hair, failure of the voice to deepen, and difficulty gaining muscle mass, even with exercise.

Puberty-onset hypogonadism can lead to:

Symptoms of adult-onset hypogonadism include:

Hypogonadism in a male refers to a decrease in either or both of the two major functions of the testes: sperm production and testosterone production.

This can happen for a number of reasons.

In primary hypogonadism, the testicles do not respond to hormone stimulation. This can be due to a congenital disorder such as Klinefelters syndrome, or acquired as a result of radiation treatment, chemotherapy, mumps, tumors or trauma to the testes.

In secondary hypogonadism, a disease state interferes with either the hypothalamus or pituitary gland, the main glands that release hormones to stimulate the testes to produce testosterone.

Situations that can cause secondary hypogonadism include:

Andropause is sometimes used to describe decreased testosterone due to the normal aging process. Testosterone levels in males increase until the age of 17 years. Then, starting at approximately 40 years of age, testosterone levels begin to decline at 1.2-2 percent per year.

Risk factors for hypogonadism include type 2 diabetes, obesity, renal failure, HIV, hypertension, chronic obstructive pulmonary disease (COPD) and taking glucocorticoid (steroids), opioid or antipsychotic medication therapy.

Testosterone replacement therapy (TRT) is the recommended treatment for male hypogonadism.

It is normally given as a topical gel, transdermal patch, or by injection. Oral forms of testosterone are not used due to the high risk of side effects, such as upset stomach.

TRT can eliminate many, if not all, of the signs and symptoms of male hypogonadism.

Benefits include:

However, there are a few risks associated with it.

It may lead to worsening of benign prostatic hyperplasia (BPH), acceleration of pre-existing prostate cancer, and worsening of both sleep apnea and congestive heart failure. TRT should not be started without first attending to these conditions.

All males who are using TRT require ongoing medical evaluation to determine adequate response to treatment. This will include regular blood tests and periodic digital rectal exams.

TRT is contraindicated in men with erythrocytosis, a condition involving a high volume percentage of red blood cells in the blood.

The response to TRT is individualized, and testosterone levels are not an indicator of who will respond to TRT and who will not. It is also worth noting that while it can relieve symptoms of hypogonadism, TRT does not restore fertility.

Hypogonadism can also affect females. In women with hypogonadism, the ovaries produce low levels of female sex hormones. This affects the functioning of the ovaries and the reproductive system.

Symptoms include delayed puberty and a lack of menstruation or irregular menstruation. Breasts may not develop fully and height may be affected. This may be due to a genetic problem, an autoimmune condition, or a range of environmental factors.

After puberty, a wide range of factors can lead to hypogonadism, including tumors, eating disorders, genetic problems, and surgery, such as a hysterectomy.

Symptoms will include hot flashes, mood changes, changes in energy levels, and discontinued menstruation.

Some lifestyle changes can help boost testosterone levels.

These include:

The measures can help maintain normal testosterone levels.

If an individual is at risk of or may have hypogonadism, a doctor will take a thorough medical history taken and carry out a physical examination, including blood tests.

Two key blood tests must be carried out to confirm the presence of hypogonadism:

The normal range of these blood tests has some variability, but a reading of between 300 and 1,000 nanograms per deciliter (ng/dL) is considered normal. Levels will be below the normal range in a person with hypogonadism.

For accuracy, the blood test should be drawn between the hours of 7.00 and 11.00 in the morning on at least two occasions. Additional testing may be necessary to confirm a diagnosis of hypogonadism.

Awareness of male hypogonadism is growing, but many adult men with the condition remain undiagnosed and untreated. This may negatively influence both their quality of life in men and their life span.

Any male who thinks he may have low testosterone levels should seek medical advice, as treatment can reverse most of the symptoms and risks of male hypogonadism.

However, before starting treatment with TRT, all men should discuss the risks and benefits with their health care provider.

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Male hypogonadism: Symptoms, causes, and treatment - Medical News Today

Hypogonadism is a common condition in the male population, with a higher prevalence in older men, obese men, and men with type 2 diabetes. It is estimated that approximately 35% of men older than 45 years of age and 30-50% of men with obesity or type 2 diabetes have hypogonadism.

Testosterone is an important sex hormone in men. It is secreted by the testes and is responsible for the typical male characteristics, such as facial, pubic, and body hair as well as muscle. This hormone also helps maintain sex drive, sperm production, and bone health. The brain and pituitary gland (a small gland at the base of the brain) control the production of testosterone by the testes.

Be open with your doctor about your medical history, all prescription and nonprescription drugs you are now taking, sexual problems, and any major changes in your life. Your doctor will take a thorough history of your symptoms and then complete a physical exam, including your body hair, breast tissue, and the size and consistency of the testes and scrotum.

Your doctor will also use blood tests to see if your total testosterone level is low. The normal range depends on the lab that conducts the test. To get a diagnosis of hypogonadism, you need at least two early morning (710 AM) blood tests that reveal low testosterone in addition to signs and symptoms typical of low testosterone. The cause of hypogonadism can be investigated further by your doctor. This might include additional blood tests, and sometimes imaging such as a pituitary MRI.

Male hypogonadism is a combination of low testosterone levels and the presence of any of these symptoms:

Over time, low testosterone may cause a man to lose body hair, muscle bulk, cause weak bones (osteoporosis), low red blood cells and smaller testes. Signs and symptoms (what you see and feel) vary from person to person.

There are many causes of hypogonadism. They may involve a problem with the testes or with the signal from the brain that controls testosterone secretion. Low testosterone can result from:

Improvement of testosterone levels can improve sexual concerns, bone health, muscle and anemia (low red cells in the blood). Hypogonadism can be treated with the use of doctor-prescribed testosterone replacement therapy. This treatment is safe and can be effective for men who are diagnosed with consistently abnormal low testosterone production and symptoms that are associated with this type of androgen (hormone) deficiency.

Although testosterone replacement therapy is the primary treatment option, some conditions that cause hypogonadism, such as obesity, can be reversible without testosterone therapy. These should be addressed before testosterone therapy is contemplated. If testosterone therapy is needed, goals of treatment are to improve symptoms associated with testosterone deficiency and maintain sex characteristics.

There are many different types of testosterone therapy. Method of treatment depends on the cause of low testosterone, the patients preferences, cost, tolerance, and concern about fertility. You should discuss the different options with your physician "your partner in care" to find out which therapy is right for you.

Injections: Self or doctor administered in a muscle every 12 weeks; administered at a clinic every 10 weeks for longer-acting. Side effects: uncomfortable, fluctuating symptoms.

Gels/Solutions: Applied to upper arm, shoulder, inner thigh, armpit. Side effects: may transfer to others via skin contact must wait to absorb completely into skin.

Patches: Adhere to skin every day to back, abdomen, upper arm, thigh; rotate locations to lessen skin reaction. Side effects: skin redness and rashes.

Buccal Tablets: Sticky pill applied to gums twice a day, absorbs quickly into bloodstream through gums. Side effects: gum irritation.

Pellets: Implanted under skin surgically every 36 months for consistent and long-term dosages. Side effects: pellet coming out through skin, site infection/ bleeding (rare), dose decreasing over time and hypogonadism symptoms possibly returning towards the end of dose period.

Nasal Gel: Applied by pump into each nostril 3x a day. Side effects: nasal irritation or congestion.

Sometimes a medication called clomiphene citrate is used to treat hypogonadism, but this is not FDA approved for this indication. A thorough discussion is needed with your doctor.

You should discuss with your physician how to monitor for prostate cancer and other risks to your prostate. Men with known or suspected prostate or breast cancer should not receive testosterone therapy. You should also talk to your doctor about the risks of testosterone therapy if you have, or are at risk for, heart disease or stroke. In addition, if you are planning fertility, you should not use testosterone therapy.

You should not receive testosterone therapy if you have:

Possible risks of testosterone treatment include:

If you are treated with testosterone, your doctor will need to see you regularly, along with blood tests.Testosterone therapy is only recommended for hypogonadism patients. Boosting testosterone is NOT approved by the US Food and Drug Administration (FDA) to help improve your strength, athletic performance, physical appearance, or to treat or prevent problems associated with aging. Using testosterone for these purposes may be harmful to your health.

There is no firm scientific evidence that long-term testosterone replacement is associated with either prostate cancer or cardiovascular events. The FDA requires that you are made aware that the possibility of cardiovascular events may exist during treatment. Prostate cells are stimulated by testosterone, so be extra vigilant about cancer screenings. African American men over age 45 especially those with family history of cancer are already at risk for prostate cancer.

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Hypogonadism in Men | Endocrine Society

Background

Clinical hyposmia and anosmia are commonly seen, most frequently with either post-inflammatory, age-related, or idiopathic causes being most frequent. Actual anatomical abnormalities of the olfactory groove or olfactory bulb are far less common. A recent case report showing a possible link between congenital olfactory bulb agenesis and Wolff-Parkinson-White syndrome suggested that there may be a relationship between cardiac arrhythmia and olfactory bulb development. While Kallmann syndrome (KS) is the classic syndrome involving olfactory bulb agenesis and hypogonadotropic hypogonadism, this case report and a prior report noting isolated hypogonadotropic hypogonadism and the Wolff-Parkinson-White syndrome suggest there may be more rare associations between cardiac arrhythmia and olfactory groove abnormalities.

A retrospective study was conducted to attempt to elucidate whether there may be a link between cardiac arrhythmias and olfactory anatomical abnormalities. The olfactory bulb volume (OBV) and olfactory sulcus depth (OSD) of 44 patients with cardiac arrhythmias were compared to 43 healthy control patients. Additionally, 11 patients with acute COVID-19 were also compared in those groups. Patients were seen between September and December 2020. Available MRI images were utilized.

The average right and left olfactory bulb volume was 29.4218.17 mm3 and 25.6715.29 mm3 for patients with cardiac arrhythmia, 40.7930.65 mm3 and 38.9521.87mm3 for healthy controls, and 21.3015.23 mm3 and 17.759.63 mm3 for COVID-19 patients. The average right and left olfactory sulcus depth was 7.681.31 mm and 7.471.56 mm for patients with cardiac arrhythmia, 10.671.53 mm and 10.621.67 mm for controls, and 7.910.99 mm and 8.020.88 mm for COVID-19 patients. The right and left olfactory bulb volume difference versus controls was significant for cardiac arrhythmia patients (p=0.028 and p=0.0038) and for COVID-19 patients (p=0.047 and p=0.0029), and the right and left olfactory sulcus depth difference versus controls was significant for cardiac arrhythmia patients (p<0.0001 and p<0.0001) and for COVID-19 patients (p<0.0001 and p<0.0001). Both COVID-19 and cardiac arrhythmia patients were, on average, significantly older than controls. On multivariate analysis, cardiac arrhythmia or COVID-19 diagnosis did not significantly correlate with smaller olfactory bulb volume, but older age, cardiac arrhythmia diagnosis, and COVID-19 diagnosis did significantly correlate with smaller olfactory sulcus depth. On multivariate analysis, older age was significantly correlated with cardiac arrhythmia diagnosis and COVID-19 diagnosis.

Olfactory bulb volume and olfactory sulcus depth in both cardiac arrhythmia and COVID-19 patients appeared significantly smaller than in controls. Cardiac arrhythmia and COVID-19 patients were significantly older than controls. Age, as well as genetic predisposition, may contribute to a difference in the radiographic olfactory anatomical findings in patients with cardiac arrhythmias and COVID-19.

A recent case report [1] noted an adult patient with previously undiagnosed congenital anosmia as well as the radiographic absence of the olfactory groove/bulbs as well as Wolff-Parkinson-White syndrome. Further investigation revealed a prior case report [2] involving a patient with isolated hypogonadotropic hypogonadism, pronounced hypodontia, and the Wolff-Parkinson-White syndrome. The classic Kallmann syndrome (KS) involves hypogonadotropic hypogonadism and olfactory bulb aplasia. The presence of one of the two classic signs of Kallmann syndrome in the aforementioned case reports but not both, while both involved Wolff-Parkinson-White syndrome, prompted an investigation into whether there may be an association between cardiac arrhythmia in general and olfactory nerve abnormalities [3-7]. The gonadotropinreleasing hormone1 (GnRH) system is involved in the development of both the reproductive and olfactory systems, which may contribute to the concomitant reproductive and olfactory dysfunction seen in Kallmann syndrome patients [4,5]. Human cardiac tissue and cardiac-associated immune cells have been shown to contain GnRH receptors, and studies in cephalopods have suggested that GnRH may have receptor targets in the cardiovascular system, which may explain the possible link between cardiac arrhythmias and olfactory nerve abnormalities. Additionally, a recent study [8] on MRI and CT findings in patients with COVID-19-related anosmia noted that radiographic olfactory changes included olfactory cleft opacification, decreased olfactory bulb volumes (OBVs), and olfactory bulb signal abnormalities such as increased signal intensity, hyperintense foci, and microhemorrhages. Olfactory bulb volume and olfactory sulcus depth (OSD) have been shown to be altered in myriad conditions, from septo-optic dysplasia to depression, post-infectious anosmia/hyposmia, and many others [9-17]. This retrospective study aimed to determine whether patients with cardiac arrhythmias and patients with acute COVID-19 had decreased olfactory bulb volume and olfactory sulcus depth relative to healthy controls.

The patient data were collected through a retrospective review of the records of patients who presented to a university hospital between September 2020 and December 2020, underwent head/brain MRI, and fit the study inclusion and exclusion criteria. Between September and December 2020, the head/brain or maxillofacial MRI of 44 patients with cardiac arrhythmias, 43 healthy control patients, and 11 patients with acute COVID-19 were analyzed. Patients aged 18 years or older were included in the three groups. Cardiac arrhythmia patients were analyzed if they had a current diagnosis of any cardiac arrhythmia and had an available head/brain or maxillofacial MRI completed between September and December 2020. COVID-19 patients were analyzed if they had a current diagnosis of acute COVID-19 and had an available head/brain or maxillofacial MRI completed between September and December 2020. Healthy control patients were analyzed if they had an available head/brain or maxillofacial MRI completed between September and December 2020 and did not carry a current diagnosis of any cardiac arrhythmia, COVID-19, disorders of smell/taste, anosmia, hyposmia, or head trauma. Patient medications were analyzed to exclude patients taking medications that could cause anosmia/hyposmia such as intranasal zinc medications, topical decongestant intranasal sprays, and oral medications such as phenothiazines or nifedipine. Figure 1 shows a coronal MRI image illustrating the olfactory bulb and the olfactory sulcus. OBVs were calculated using volumetric analysis of the olfactory bulb on T2 MRI sequences as previously described [12] using the 3D Slicer software ver. 4.10.2 (http://www.slicer.org/). The 3D slicer software is a free, open-source software package for the analysis of medical imaging developed by Harvard University and facilitated volumetric analysis of the olfactory bulb data. The olfactory bulbs were segmented by tracing their outlines manually, and the software ran a quantification process that rendered the volume of the olfactory bulb. OSD was measured as described previously [8] on coronal T2 images by measuring the depth to the deepest point of the olfactory sulcus along a line tangent to the inferior borders of the gyrus rectus. In addition to patient diagnosis and olfactory bulb volume and sulcus depth, data on patient age and gender were compared. Patient data were de-identified and retrospective, and this study was approved by the SUNY-Upstate Institutional Review Board (1427574-1).

Patient data were compiled in Microsoft Excel (Microsoft Corporation, Redmond, Washington, USA) and the data were analyzed using XLSTAT (Addinsoft, Paris, France). Continuous variables were analyzed using the Students t-test and one-way analysis of variance (ANOVA) for comparison between groups. The Pearson Correlation/Association test was also utilized to determine the correlation between the observed data variables. Multivariate analysis was conducted via logistical regression using XLSTAT, utilizing a Newton-Raphson algorithm. The level of statistical significance was set at p < 0.05.

Table 1 shows the patient characteristics for each group. Of the 44 cardiac arrhythmia patients, 38 had atrial fibrillation only, one had atrial fibrillation and supraventricular tachycardia, three had atrial flutter, one had sick sinus syndrome, and one had prolonged Q-T syndrome. Table 2 shows the olfactory bulb volume and olfactory sulcus depth, patient age, and patient sex data and univariate analysis data for the three patient groups. The average right and left olfactory bulb volume was 29.4218.17 mm3 and 25.6715.29 mm3 for patients with cardiac arrhythmia, 40.7930.65 mm3 and 38.9521.87mm3 for healthy controls, and 21.3015.23 mm3 and 17.759.63 mm3 for COVID-19 patients. The average right and left olfactory sulcus depth was 7.681.31 mm and 7.471.56 mm for patients with cardiac arrhythmia, 10.671.53 mm and 10.621.67 mm for healthy controls, and 7.910.99 mm and 8.020.88 mm for COVID-19 patients. The right and left olfactory bulb volume difference versus controls was significant for cardiac arrhythmia patients (p=0.028 and p=0.0038) and for COVID-19 patients (p=0.047 and p=0.0029), and the right and left olfactory sulcus depth difference versus controls was significant for cardiac arrhythmia patients (p<0.0001 and p<0.0001) and for COVID-19 patients (p<0.0001 and p<0.0001). Multivariate analysis via XLSTAT utilizing logistical regression of the data using an iterative algorithm using the Newton-Raphson algorithm was performed. The multivariate analysis data are shown in Table 3. On multivariate analysis, age (p=0.001) and cardiac arrhythmia diagnosis (p=0.0001) or COVID-19 diagnosis (p=0.0001) remained significant predictors of smaller olfactory sulcus depth but not of smaller olfactory bulb volume. Patient sex was not a significant predictor of olfactory sulcus depth or olfactory bulb volume on multivariate analysis. The average age for the cardiac arrhythmia group was 76.1113.13 years (p<0.0001 vs control group), 51.8617.66 years for the control group, and 69.2717.64 years for the COVID-19 group (p=0.0005 vs. control group). Of the 44 cardiac arrhythmia patients, 28 were male and 16 were female. Of the 43 control patients, 21 were male and 22 were female. Of the 11 COVID-19 patients, six were male and five were female.

The volume of the olfactory bulbs and the depth of the olfactory sulcus are readily obtained from MRI imaging and can be used as a neuroanatomical comparative tool to assess the structure of the olfactory system in patients [18,19]. Olfactory bulb volumes and olfactory sulcus depth values [8,20] vary by patient population, MRI protocol, and measurement/calculation method but are typically on the order of 30-90 mm3 for olfactory bulb volumes and 5-10 mm for olfactory sulcus depth, similar to the average values noted in the patient population in this study. Isolated olfactory nerve agenesis is rare, as in a case report in a 12-year-old girl by Carswell et al. [21], noting a patient with congenital complete absence of the olfactory nerves. Coimbra et al. [3] also reported a similarly rare case of isolated olfactory bulb agenesis. The human olfactory apparatus develops during the fetal stage, and the developing fetus can detect odors as early as 28 weeks, and the developing olfactory bulbs can be seen on MRI at this point. Olfactory axons project from the nasal epithelium prior to the formation of the olfactory bulbs and lack a peripheral ganglion, but the synaptic structures of the future olfactory bulb have this functionality. The olfactory bulb begins to laminate at 14 weeks, but complete myelination occurs postnatally. The olfactory system does not contain direct thalamic projections, but the olfactory bulb and anterior olfactory nucleus essentially serve as thalamic surrogates. Olfactory abnormalities can be seen in children with brain malformations, endocrine disorders, chromosome anomalies, and craniofacial abnormalities [4-6]. Kallmann syndrome is a classically described syndrome presenting with congenital olfactory bulb agenesis. Kallmann syndrome is a subtype of the broader group of isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) syndromes [7]. KSconsists of hypogonadotropic hypogonadism with anosmia and a congenital absence of the olfactory bulbs. There are also less severe and somewhat more common pathologies seen in IGD, including hypothalamic amenorrhea (HA), constitutional delay of puberty (CDP), and adult-onset hypogonadotropic hypogonadism (AHH). The association between hypothalamic hypogonadism and olfactory bulb agenesis in Kallmann syndrome is thought to be related to the association between the GnRH neurons and the olfactory placode. IGD can also be related to non-reproductive features such as midline facial defects, renal agenesis, limb abnormalities, hearing loss, and eye movement and balance disorders.

Acquired olfactory dysfunction can be commonly seen in post-upper respiratory infection (URI) anosmia or hyposmia [10]. Studies have shown that olfactory bulb volume and olfactory sulcus depth decreased in patients with olfactory loss after URI compared to normal controls. Studies have also shown that there may be significant gray matter volume loss in the right orbitofrontal cortex (OFC) in patients with post-infectious olfactory disfunction and that there may be a significant negative correlation between the volume of gray matter in the right OFC as well as olfactory bulb volume with the duration of olfactory loss in these post-infectious olfactory loss patients versus normal controls. Kandemirli et al. [8] examined olfactory function and CT and MRI findings in patients with persistent COVID-19 olfactory dysfunction. They evaluated olfactory function with the Sniffin' Sticks test and collected quantitative measurements of olfactory bulb volumes, olfactory sulcus depths, and olfactory radiographic characteristics. They noted frequent olfactory cleft opacification (~73.9% of cases), subnormal olfactory bulb volumes in ~43.5% of cases, and shallow olfactory sulci in ~60.9% of cases. They also noted frequent abnormalities in olfactory bulb shape, olfactory bulb signal intensity, and frequent microhemorrhages and abnormalities in the clumping of or scarcity of olfactory filia. Studies have also shown that olfactory bulb volume can be decreased in patients with depression, after transsphenoidal pituitary surgery, in patients with Parkinsons disease, and that olfactory bulb volume can be decreased in women and with increasing age [11-17].

In this study, olfactory bulb volume and olfactory sulcus depth in patients with cardiac arrhythmia, acute COVID-19, and healthy controls were measured. Patients with cardiac arrhythmia and COVID-19 had significantly smaller right and left olfactory bulb volumes and olfactory sulcus depths than controls on univariate analysis and were significantly older than controls. On multivariate analysis, olfactory bulb volume did not correlate significantly with cardiac arrhythmia diagnosis or COVID-19 diagnosis. On multivariate analysis, smaller right and left olfactory sulcus depth did significantly correlate with cardiac arrhythmia and COVID-19 diagnosis. On multivariate analysis, older age was also significantly correlated with cardiac arrhythmia and COVID-19 diagnosis. This may indicate that there may be a correlation between the propensity to develop cardiac arrhythmia and the propensity for olfactory dysfunction or atrophy of the olfactory bulb and/or olfactory sulcus over time. This study's limitations include its retrospective nature, which introduces the possibility of recall and selection bias. Given the retrospective nature of this study, there was some heterogeneity in the MRI studies/sequences available for patients in this study. A prospective study in which all patients had a uniform fine-cut MRI protocol standardized for the study protocol and specifically targeted at the olfactory anatomy would be helpful. Additionally, the relatively low patient numbers are a limitationand may limit power in the statistical analysis. Patient medication lists were screened to exclude patients on intranasal or oral medications that may affect olfaction, but the use of medications not reported by patients and not present in the medical record or use of other patient medications that might unknowingly affect olfaction is another possible limitation. The mild diversity in the arrhythmia types in the cardiac arrhythmia group (although the vast majority were atrial fibrillation patients) and the mild heterogeneity in the diagnoses of the control group may also limit the statistical analysis. Future prospective studies with larger patient numbers and a greater diversity of other cardiac arrhythmia types with distinct statistical analyses for each arrhythmia type (e.g., a large number of purely Wolff-Parkinson-White patients) would be of use. The significantly older age of the cardiac arrhythmia and COVID-19 patients may also act as a confounder, and indeed, on multivariate analysis, older age did significantly correlate with smaller olfactory sulcus depth, as did cardiac arrhythmia diagnosis and COVID-19 diagnosis. This may indicate that cardiac arrhythmia, COVID-19 diagnosis or susceptibility, and older age may all correlate significantly with small olfactory sulcus depth, and that older age is also independently correlated with a propensity for cardiac arrhythmia. Additionally, the collection and availability of a formal, standardized olfactory function measurement in all patients, such as Sniffin sticks or the Pittsburgh Smell Identification test, would also allow useful correlation between functional/clinical olfactory data (quantitative olfactory measurements) and radiographic olfactory bulb volume and olfactory sulcus depth data.

This retrospective radiographic study demonstrated smaller olfactory bulb volumes and olfactory sulcus depths on MRI in patients with a history of cardiac arrhythmia and patients with COVID-19 compared to healthy control patients. Cardiac arrhythmia and COVID-19 patients were significantly older than controls. Multivariate analysis demonstrated that cardiac arrhythmia diagnosis and COVID-19 diagnosis, as well as older age, were all significantly associated with smaller olfactory sulcus depth but not with smaller olfactory bulb volume. Future prospective studies with standardized MRI protocols and larger groups of patients with cardiac arrhythmias and larger numbers of healthy controls may help elucidate whether there is a correlation between a predisposition to cardiac arrhythmia and radiographic abnormalities in the olfactory bulb/olfactory sulcus.

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Olfactory Radioanatomical Findings in Patients With Cardiac Arrhythmias, COVID-19, and Healthy Controls - Cureus