Late Onset Hypogonadism (Andropause)

Introduction:

Andropause, better termed as Late onset hypogonadism (LOH):

Andropause is also called Late-onset hypogonadism (LOH), Age-onset hypogonadism (AOH) and previously called age-related hypogonadism, PADAM (Partial Androgen Deficiency in Aging Male), ADAM (Androgen Decline in the Aging Male), TDS (Testosterone Deficiency Syndrome) or low T syndrome. The current terminology used to describe this disorder is Late Onset Hypogonadism or LOH.

The terms “male menopause” and “andropause” are used in the popular media and are misleading, as they imply a sudden change in hormone levels similar to what women experience in menopause, unlike in males when there is a gradual change both in symptoms and the hormonal milieu.

The term Late‐onset hypogonadism (LOH) was coined in 2002 and defined as “a clinical and biochemical syndrome associated with advancing age, characterized by symptoms AND a deficiency in serum testosterone”. It is defined by reduced serum testosterone levels (either total testosterone or free testosterone) and the careful exclusion of any form of other classical hypogonadism. When the androgen decline associated with advancing age causes detrimental physiological and mental effects, the syndrome is known as symptomatic LOH (SLOH). In fact, LOH is a consequence of the combination of the aging process, deterioration of hypothalamic-pituitary function, and Leydig cell function in the testes.

The Sexual Medicine Society of North America defines Late Onset Hypogonadism as a clinical and biochemical syndrome characterized by a deficiency of testosterone (T) with symptoms and signs that can be caused by testicular and/or hypothalamic-pituitary (HP) dysfunction; LOH is therefore clinically distinct from classical primary and secondary hypogonadism. This syndrome is characterized by T deficiency and the failure to mount an adequate compensatory pituitary response to low T levels; gonadotropin levels are low or in the normal range.

A detailed medical history and physical examination are the basis of the diagnosis, and should always precede any biochemical investigations.

There is no universally-accepted lower limit of “normal range” for total testosterone. Based on the consensus reached in 2009 by representatives of leading societies concerned with the problem of hypogonadism in men: the American Society of Andrology (ASA), the International Society of Andrology (ISA), the International Society for the Study of Aging Male (ISSAM), the European Association of Urology (EAU), and the European Academy of Andrology (EAA), the lowest norm for total testosterone levels in older men could not be clearly defined.

In other words, general screening of asymptomatic people or men above a certain age for testosterone levels is not feasible, and should not be used to detect LOH cases.

LOH may often be underdiagnosed and often untreated. But recently there have been concerns of over-diagnosis and unnecessary treatment of this condition with testosterone replacement, which has come by as a result of only viewing the testosterone levels done by screening asymptomatic individuals without a proper detailed history for symptoms that are actually related to LOH itself. Since these symptoms may also have origins other than LOH, exclusion of other disease entities and subnormal serum testosterone levels are considered prerequisites for the diagnosis and possible treatment of LOH. During the past decade these guidelines were often neglected and, especially in the USA, indiscriminate prescribing of testosterone was widely practiced to such an extent that the US FDA warned against such irresponsible behavior.

For this, in March 2015, the U.S. Food and Drug Administration (FDA) issued a drug safety communication cautioning about the use of T products for low T levels as a result of aging and required US manufacturers of prescription T products to amend drug labels to include warnings of possible increased risk of heart attack and stroke. Prescribing information was amended to indicate that T is appropriate for replacement only in adult men with low T levels because of damage or trauma to the testes (ie, orchitis, Klinefelter syndrome, etc), because of gonadotropin or LHRH deficiency, or because of damage to the pituitary or the hypothalamus. Testosterone treatment was not recommended for men who do not fall into these categories (ie, men with AOH).

In summary, symptomatic LOH must be due to symptoms related to LOH, and not due to the aging process alone. This syndrome is not classical primary (testicular failure) or secondary (pituitary or hypothalamic failure) hypogonadism because it may have elements of both presentations.

Pathophysiology:

Unlike menopause in females where there is an abrupt disruption in circulating female hormones, LOH / andropause specifically is related to the aging man and the gradual reduction of circulating male hormones (androgens) in the body resulting in symptoms related to this reduction in male hormones.

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. The serum testosterone concentration gradually declines across the lifespan and the symptoms between aging and hypogonadism overlap.

The age for men to suffer from symptomatic LOH varies widely, and the diagnostic confirmation of this would be based on both symptomatic LOH and lab results taken together into consideration.

Testosterone threshold at which symptoms become manifest show subject-to-subject variation and many men do not show any symptoms, although having low levels of testosterone.

For years, there has been major disagreement on how to define the syndrome for clinical and epidemiologic research purposes due to the varied levels of testosterone in different individuals and the actual pre-defined levels by which an individual will actually suffer symptoms as a result of this. Hence LOH would come by to be defined based on both a combination of symptoms and a low testosterone level which attributes to the symptoms in an aging male.

Other causes of low testosterone levels in men:

Acute illness like head trauma, stroke, myocardial infarction, gall bladder surgery, or acute colitis can also reduce testosterone synthesis. This effect can last for a few days to several weeks. Acute severe burns can result in lower testosterone levels for eight or more weeks. For this reason, caution is necessary in making a diagnosis of testosterone deficiency during, or in the weeks immediately following, an episode of acute illness.

Diagnosis:

The diagnosis can only made AFTER a review of the symptoms by the doctor concerned.

Common clinical symptoms are lethargy, fatigue, decreased sense of well-being, reduced physical and mental activity, diminished libido, increased sweating, depressive mood, reduced muscle and bone mass or even osteoporosis, erectile dysfunction, , decreased muscle strength, hot flashes, gynaecomastia and decreased testicular volume, low-energy fractures and mild anemia . Non-specific symptoms include decreased self-confidence, motivation, depression and irritability, memory and concentration impairment, sleep disorders or insomnia, and decreased psychomotor activity.

Symptoms of adult-onset hypogonadism in males include:

Erectile dysfunction

Depressed mood

Decreased libido

Lethargy

Sleep disturbances

Decreased muscle mass and strength

Loss of body hair (pubic, axillary, facial)

Osteoporosis and decreased bone mineral density

Increased body fat

Breast discomfort and enlargement

Hot flashes

Sweating

Poor concentration and decreased energy

When clinical symptoms are present, the laboratory work-up should focus on total testosterone serum levels. Total testosterone levels <230 ng/dl (<8 nmol l^–1) indicate hypogonadism. In cases of testosterone levels between 230 and 320 ng/dl (8 – 11 nmol l^–1), measurement should be repeated and supplemented by determination of free testosterone, either by appropriate laboratory methods or the calculation of free testosterone index. In case of very low testosterone levels, classical secondary hypogonadism needs to be considered and excluded.

For the safety reasons and to exclude contraindications of therapy with testosterone replacement therapy, and for follow-up investigations during therapy, prostate-specific antigen (PSA), hemoglobin, hematocrit and lipid profile are of interest. Prior to treatment of symptomatic LOH, prostate and breast cancer in males should be excluded.

Risk factors:

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

The development of chronic illnesses, including diabetes, cardiovascular disease and inflammatory disorders, is associated with an accelerated rate of aging-related testosterone decline, ranging between 1.5- and 3.6-fold compared to men who remain disease-free. Individuals with BMI (body mass index) ≥30 kg/m² are at 13-fold increased risk of LOH compared to those with BMI <25 kg/m^2.

Management of LOH:

It is pertinent to note that prevention or reducing the risk factors are an important element in managing this disorder.

Some men in their late 40s and early 50s can develop depression, loss of libido, erectile dysfunction, and other physical and emotional symptoms such as irritability, loss of muscle mass and reduced ability to exercise, weight gain, lack of energy, difficulty sleeping, or poor concentration; many of these symptoms may arise from midlife crisis or as the results of a long-term unhealthy lifestyle (smoking, excess drinking, overeating, lack of exercise) and may be best addressed by lifestyle changes, therapy, or antidepressants.

Lifestyle changes include a healthy diet, regular exercise and to stop smoking and prevent overeating. Early identification and treatment of risk factors for LOH is vital. In overweight or obese men, lifestyle counseling to achieve sustained weight loss should be the mainstay of management, even if testosterone treatment is likely to induce a small increase of the total lean body mass and a small decrease of total body fat.

The diagnosis of LOH requires the presence of symptoms and signs suggestive of testosterone deficiency. If a person has symptoms of late-onset hypogonadism, testosterone is measured by taking blood in the morning on at least two days. The European Male Ageing Study (EMAS) has defined the strict diagnostic criteria for LOH to include the simultaneous presence of reproducibly low serum testosterone (T) [either repeated (at least twice) serum total T level <8 nmol l^–1, or serum total T of 8–11 nmol l^–1 and free T <220 pmol l^–1]. (Total T <11 nmol l⁻¹ and free T <220 pmol l⁻¹) and three sexual symptoms (erectile dysfunction, and reduced frequency of sexual thoughts and morning erections). By these criteria, only 2% of 40- to 80-year-old men truly have LOH.

When hypogonadism is present, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) will be measured to distinguish between primary hypogonadism (low testosterone, high LH and FSH) and secondary hypogonadism (low testosterone, normal or reduced LH and FSH).

There is general agreement amongst various professional bodies that in the evaluation of LOH, the total testosterone level above 12 nmol/l (350 ng/dl) does not require substitution. Similarly, based on the data of younger men, there is consensus that patients with serum total testosterone levels below 8 nmol/l (230 ng/dl) will usually benefit from testosterone treatment.

Due to difficulty and expense of testing, and the ambiguity of the results, screening of asymptomatic individuals is not recommended.

Risk factors like type 2 diabetes, obesity, renal failure, hypertension and chronic obstructive pulmonary disease (COPD) need to be treated, and require life style changes.

After the diagnosis of LOH is made, possible causes for low testosterone such as obesity, metabolic syndrome and chronic diseases should be investigated, and if present, adequately treated.

Absolute contraindications for testosterone treatment include prostate and breast cancer. Relative contraindications are a serum prostate specific antigen (PSA) level >4 ng ml^–1 (or 3 ng ml^–1 in men with increased risk for prostate cancer, such as those of African descent or with first degree relatives with a history of prostate cancer), a hematocrit >50%, severe lower urinary tract symptoms caused by benign prostatic hypertrophy (as defined by an International Prostate Symptom Score (IPSS) higher than 19), untreated or poorly controlled congestive heart failure and untreated sleep apnea.

Testosterone replacement should be offered to the LOH patient only after sufficient counseling, informing him on the long-term beneficial and adverse effects of this treatment.

Types of testosterone replacement

The types of testosterone replacement therapy that are available include:

• various forms of gel,
• skin patch,
• scrotal patch,
• gum and cheek patch (mouth patch at buccal cavity),
• injection therapy and
• Implantable pellets.

The skin patch, scrotal patch and gels are applied once a day, the mouth patch applied twice a day, and injections monthly to 3 monthly.

It should be noted that testosterone therapy is not recommended for men planning fertility in the near term, with breast or prostate cancer, with a palpable prostate nodule or induration, a prostate-specific antigen (PSA) level >4.0 ng/mL (or >3.0 ng/mL with a high risk of prostate cancer), elevated hematocrit (>48% or >50% for men living at high altitude), untreated obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia.

For men >65 years who meet the diagnostic criteria for hypogonadism, testosterone therapy can be offered after individualized discussion of the risks and benefits.

For patients who have been started on testosterone therapy, they should be monitored and should be evaluated for its therapeutic effect, serum testosterone levels, hematocrit, and PSA levels several times during the first year of therapy and annually thereafter.

For any aging male who does feel they have symptoms of LOH, they should preferably see the urologist to determine if they fit the criteria for LOH, determine underlying risk factors and the life style management, and determine if after evaluation, treatment of underlying risk factors, whether they are a suitable candidate for testosterone replacement therapy.

Postamble and summary – take home message:

1. LOH (Late onset hypogonadism / Andropause) is a clinical and biochemical syndrome characterized by a deficiency of testosterone (T) with symptoms and signs that can be caused by testicular and/or hypothalamic-pituitary (HP) dysfunction
2. There is no universally-accepted lower limit of “normal range” for total testosterone.
3. Symptomatic LOH must be due to symptoms related to LOH and not the ageing process alone. In other words, low testosterone levels seen in the aging male does not mean a person suffers from LOH. The person must have symptoms attributed to low testosterone level AND biochemical low testosterone levels.
4. A detailed medical history and physical examination are the basis of the diagnosis, and should always precede any biochemical investigations.
5. LOH (Late onset hypogonadism / Andropause) may often be underdiagnosed and often untreated, but recently, there have been concerns of over-diagnosis and unnecessary treatment of this condition with testosterone replacement.
6. In March 2015, the U.S. Food and Drug Administration (FDA) issued a drug safety communication cautioning about the use of T (testosterone) products for low T levels as a result of aging and required US manufacturers of prescription T products to amend drug labels to include warnings of possible increased risk of heart attack and stroke.
7. General screening of asymptomatic people or men above a certain age for testosterone levels is not feasible and should not be used to detect LOH cases.

8. Testosterone therapy is not recommended for men planning fertility in the near term, with breast or prostate cancer, with a palpable prostate nodule or induration, a prostate-specific antigen (PSA) level >4.0 ng/mL (or >3.0 ng/mL with a high risk of prostate cancer), elevated hematocrit (>48% or >50% for men living at high altitude), untreated obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia.

It is best for your doctor to confirm a diagnosis of LOH based on the testosterone level AND symptoms, and to decide further management after a thorough evaluation. One should not self-treat this disease with the assumption that he suffers from LOH.

Ahad, Disember 09, 2007

Hipogonadisme: Kurang hormon seks

Utusan OnLine:

Published on: 09/12/2007

KITA mungkin biasa mendengar lelaki mengalami masalah mati pucuk (disfungsi erektil) iaitu keadaan berkaitan dengan kemampuan seks, namun jarang didedahkan dengan hipogonadisme – satu lagi masalah berkaitan seks yang menyerang lelaki tidak kira usia. Apakah sebenarnya hipogonadisme?

Menurut Pakar Urologi dan Pembedahan Urologikal, Dr Rajeentheran Suntheralingam, hipogonadisme lelaki adalah keadaan di mana badan tidak menghasilkan hormon seks testosteron yang mencukupi. Sebanyak lima juta lelaki di Amerika Syarikat dikatakan tidak menghasilkan hormon testosteron yang cukup, iaitu hormon yang memainkan peranan dalam tumbesaran dan perkembangan kelelakian ketika baligh.

Kesan testosteron bermula ketika janin lagi di mana ia akan merangsang pembentukan organ seks lelaki. Hormon ini berterusan memainkan peranan penting ketika baligh dan dewasa dengan membentuk karakter lelaki dan mengekalkan keinginan seks.

‘‘Anda mungkin dilahirkan dengan hipogonadisme atau ia boleh berkembang kemudian disebabkan oleh kecederaan atau jangkitan,’’ katanya. Ujarnya lagi, kesan hipogonadisme dan apa yang anda boleh lakukan untuk mengatasinya bergantung kepada punca dan pada ketika mana ia berlaku.

Namun begitu kata Dr. Rajeentheran, jika hipogonadisme berlaku selepas baligh, perkembangannya lebih kepada menyebabkan masalah sementara yang boleh diatasi melalui rawatan. Sesetengah jenis hipogonadisme boleh dirawat dengan terapi gantian testosteron.

Tanda-tanda dan simptom

Hipogonadisme boleh berlaku ketika perkembangan janin, baligh atau dewasa. Bergantung pada ketika mana ia berkembang, tanda-tanda dan simptomnya berbeza. Jika badan tidak menghasilkan testosteron yang cukup ketika perkembangan janin, tumbesaran organ seks luar akan terjejas. Kanak-kanak yang secara genetiknya lelaki mungkin akan lahir dengan alat kelamin perempuan, alat kelamin kabur (sama ada tidak jelas lelaki atau perempuan) ataupun alat kelamin lelaki yang tidak berkembang.

Manakala jika ia berlaku ketika baligh pula, hipogonadisme akan memperlahankan tumbesaran dan mengganggu perkembangan. Ia menyebabkan penurunan perkembangan jisim otot, suara tidak bertukar menjadi parau, pertumbuhan bulu badan terjejas, pertumbuhan zakar dan buah zakar terjejas, perkembangan berlebihan bahagian lengan dan paha dan juga perkembangan tisu buah dada (ginekomastia).

Dan, jika hipogonadisme menyerang ketika dewasa, beberapa karakter fizikal maskulin akan terganggu dan sekali gus menjejaskan fungsi reproduksi normal.

Tanda-tanda dan simptom termasuk

* Disfungsi erektil (mati pucuk)

* Ketidaksuburan

* Penurunan pertumbuhan bulu badan dan janggut

* Pertambahan lemak dan penurunan jisim otot serta kekurangan jisim tulang (osteoporosis)

* Penurunan saiz atau kekenyalan buah zakar

* Perkembangan tisu buah dada (ginekomastia)

* Hipogonadisme juga boleh menyebabkan perubahan emosi dan mental. Ketika testosteron menurun, sesetengah lelaki akan mengalami simptom serupa seperti wanita menopaus.

Ini termasuk letih, kurang keinginan seks (libido), sukar menumpu perhatian, radang, resah dan juga murung.

Punca

Terdapat dua jenis utama hipogonadisme :

1. Primer – Juga dikenali sebagai kegagalan testikular utama berlaku disebabkan masalah pada buah zakar.
2. Sekunder – Ia berlaku disebabkan masalah pada hipotalamus atau kelenjar pituitari (bahagian otak yang memberi arahan kepada buah zakar menghasilkan testosteron).

Hipotalamus menghasilkan hormon pembebasan gonadotropin, yang memberi arahan kepada kelenjar pituitari untuk menghasilkan hormon penghasilan folikel (FSH) dan hormon luteinizing. Hormon ini kemudian memberi arahan kepada buah zakar menghasilkan testosteron.

Hipogonadisme primer

Punca utama termasuk:

* Sindrom Klinefelter: Keadaan ini menyebabkan ketidaknormalan sejak lahir pada kromosom seks, X dan Y. Lelaki biasanya mempunyai satu kromosom X dan satu kromosom Y.

Dalam kes ini, dua atau lebih kromosom X hadir sebagai tambahan kepada satu kromosom Y. Kromosom Y mengandungi material genetik yang menentukan jantina bayi dan berkaitan dengan perkembangan. Kromosom X berlebihan yang berlaku pada pesakit sindrom Klinefelter menyebabkan perkembangan tidak normal buah zakar.

* Buah zakar tidak keluar: Ketika dalam kandungan, buah zakar berkembang dalam abdomen dan biasanya turun ke bawah di dalam skrotum dua bulan sebelum lahir.

Dalam kes ini satu atau dua buah zakar tidak keluar ketika lahir. Keadaan ini biasanya pulih sendiri dalam masa beberapa tahun pertama tanpa sebarang rawatan. Jika ia tidak pulih sendiri ketika kanak-kanak, ia menyebabkan buah zakar tidak berfungsi dan mengurangkan pengeluaran hormon testosteron.

* Beguk Orkitis: Jika jangkitan beguk melibatkan buah zakar ketika dewasa, kerosakan testikular jangka panjang akan berlaku.

* Hemokromatosis: Kandungan besi yang terlalu tinggi dalam darah boleh menyebabkan kegagalan buah zakar atau disfungsi kelenjar pituitari yang mengganggu penghasilan testosteron.

* Kecederaan buah zakar: Kerana lokasinya di luar abdomen, buah zakar terdedah kepada kecederaan.

Kerosakan pada buah zakar yang telah berkembang menyebabkan hipogonadisme. Bagaimanapun kerosakan pada sebelah buah zakar tidak mengganggu penghasilan testosteron.

* Rawatan kanser: Kemoterapi atau terapi radiasi untuk rawatan kanser boleh mengganggu penghasilan testosteron dan sperma.

Kesan kedua-dua rawatan biasanya hanya sementara, namun ketidaksuburan kekal boleh berlaku. Walaupun banyak lelaki mendapat balik kesuburan mereka dalam masa beberapa bulan selepas rawatan berakhir, menyimpan sperma sebelum memulakan rawatan kanser adalah langkah yang digalakkan.

* Faktor usia

Semakin meningkat usia, penghasilan testosteron semakin perlahan dan berkurangan. Kadar pengurangan testosteron berbeza setiap lelaki. Sebanyak 30 peratus lelaki berusia lebih 75 tahun mempunyai paras testosteron rendah di bawah normal.

Hipogonadisme sekunder

Dalam kes ini, buah zakar adalah normal tetapi tidak berfungsi dengan betul berikutan masalah pada pituitari atau hipotalamus. Beberapa keadaan boleh menyebabkan hipogonadisme sekunder termasuk:

* Sindrom Kallman: Perkembangan abnormal hipotalamus.

* Masalah pituitari: Ketidaknormalan pada kelenjar pituitari menjejaskan pengeluaran hormon dari kelenjar pituitari ke buah zakar, memberi kesan kepada pengeluaran normal testosteron.

Tumor pituitari atau lain-lain jenis tumor otak terletak berdekatan dengan kelenjar pituitari menyebabkan gangguan hormon testosteron atau hormon lain. Juga rawatan untuk tumor otak seperti pembedahan atau terapi radiasi akan menjejaskan fungsi pituitari.

* Penyakit radang: Sesetengah penyakit radang seperti sarkoidosis, histiositosis, tuberkulosis dan sesetangah jangkitan kulat melibatkan hipotalamus dan kelenjar pituitari mengganggu pengeluaran testosteron.

* HIV/AIDS: Virus ini menyebabkan paras testosteron rendah dengan mengganggu hipotalamus, pituitari dan buah zakar.

* Perubatan: Pengambilan beberapa jenis dadah seperti ubat tahan sakit opiat dan sesetengah hormon boleh mengganggu pengeluaran testosteron.

* Kegemukan

Adakah hipogonadisme boleh diwarisi?

Ya, ia boleh diwarisi. Jika terdapat sejarah keluarga yang mempunyai hipogonadisme, beritahu doktor anda. Yang penting kesedaran dan sentiasa berjaga-jaga dengan tanda-tanda atau simptom hipogonadisme.

Bila patut berjumpa doktor?

Jumpa doktor apabila mempunyai sebarang simptom hipogonadisme. Mengenal pasti punca hipogonadisme adalah langkah penting utama untuk mendapatkan rawatan yang perlu. Anda perlu berjumpa pakar endokrinologi, pakar dalam bidang kelenjar hormon pengeluaran (endokrin). Jika doktor penjagaan primer anda mengesyaki mana-mana simptom berlaku, anda akan dirujuk kepada endokrinologis. Atau anda boleh meminta sendiri untuk merujuk kepada pakar.

Pemeriksaan dan diagnosis

Doktor akan memeriksa paras testosteron dalam darah jika anda ada sebarang tanda atau simptom hipogonadisme. Pemeriksaan dan rawatan awal membolehkan pencegahan lebih baik melawan osteoporosis dan keadaan lain yang berkaitan. Doktor melakukan diagnosis berdasarkan simptom hipogonadisme dan keputusan ujian darah yang menentukan paras testosteron. Kerana paras testosteron berbeza dan secara umumnya tinggi di waktu pagi, ujian darah biasanya dibuat awal pagi.

Jika ujian mengesahkan anda mempunyai testosteron rendah, ujian selanjutnya akan menentukan masalah pada buah zakar atau ketidaknormalan pituitari adalah puncanya. Berdasarkan simptom dan tanda-tanda spesifik, kajian tambahan boleh menentukan puncanya. Ujian ini termasuk ujian hormon, analisis semen (air mani), imbasan pituitari, kajian genetik dan biopsi buah zakar.

Ujian testosteron juga memainkan peranan penting dalam menentukan hipogonadisme. Ini membantu doktor menentukan dos yang betul untuk rawatan.