Hormones and Male Infertility

Hormones Measured in the Evaluation of Male Infertility and Their Interpretation

Hormones play a critical role in spermatogenesis. The testis has 2 primary functions:

1. Testosterone production

2. Sperm production

Both of these are under hormonal control by the brain and there is an expected relationship between the hormone levels secreted by the brain and those secreted by the testis.. Problems with either of these functions can sometimes be detected by blood tests which can help localize if the brain, the testis and/or the reproductive tract (the pipes which carry sperm from testis to penis) is the problem.

The basic hormone evaluation includes:

1. Testosterone

2. Follicle stimulating hormone (FSH)

3. Prolactin (PRL)

4. Optional: Estradiol, Thyroid Stimulating Hormone (FSH), Estradiol

Figure: Negative feedback loop between the brain and testis. The testis produces (1) testosterone and (2) sperm. The brain has 'sensors' for testosterone and sperm production (the latter is indirectly reflected in levels of inhibin B - a hormone which is decreased if sperm production is diminished, that is, Inhibin B 'inhibits secretion of FSH'). The brain attempts to maintain constant levels of testosterone and sperm produced by the testis by adjusting the levels of 2 hormones which affect testicular function in response to the levels of testosterone and inhibin B in the blood.

• If testosterone is lower than desired, the brain increases secretion of luteinizing hormone; conversely, if testosterone levels are too high, it decreases LH secretion. The testis usually responds to increased LH levels by increasing testosterone and to low LH levels by decreasing testosterone.

• In the same way, the brain will increase FSH levels if inhibin B levels are decreased in response to decreased sperm production or increase them if inhibin B levels are low.

 The 3 common patterns of hormonal abnormalities.

Pre-testicular problems are those associated with impaired hormone secretion by the brain. The expected response of the brain to low testosterone or sperm production is missing.

Testicular problems are those which originate within the testis themselves. The brain responds appropriately by increasing LH, FSH or both in reponse to low testosterone or decreased sperm production, respectively.

Post-testicular problems are those in which the brain and testis OK (sperm and testosterone are being produced normally), but the pipes blocked and sperm are absent from the ejaculate.

One important thing to note about measurements of LH and FSH is that increased levels are very specificfor testicular dysfunction, but relatively insensitive. A lack of sensitivity means that normal levels of LH and FSH do not exclude the presence of a testicular problem. High specificity means that if LH and FSH are elevated it means that a problem is definitely present.

Testosterone

Testosterone is the primary male sex hormone. Small amounts of testosterone are produced in females. The vast majority of testosterone is produced in the testicle but small amounts are also produced in the adrenal glands. Leuteinizing hormone (LH) stimulates production of testoterone by the Leydig cells of the testis - high levels of LH imply that the testis is not producing satisfactory amounts.

High levels of testosterone within the testes are critically important for sperm production. The levels of intratesticular testosterone required for sperm production are about 10 times higher than those in the blood stream (much higher than can safely be achieved with the administration of testosterone). 

Testosterone administered from outside the body (exogenous testosterone) for the purposes of supplementation of body building can achieve high levels of blood testosterone but are not capable of reproducing the high levels of testicular testosterone. Exogenous testosterone can, however, fool the brain into thinking that the testes are doing a good job and consequently 'turn off' testosterone production within the testis with the effect of also turning off sperm production. 

*As of 2018, nasally administered testosterone (Natesto) has become available. This has more frequent dosing and as a consequence, it seems to maintain the normal secretion of gonadotropins. Spermatogenesis does not seem to be adversely affected (European Urology Focus March 2018). Speak to your urologist about this.

While administration of exogenous testosterone is generally contraceptive, there are ways in which the testis can be encouraged to make more testosterone. Note that these approaches are usually not effective if the testosterone level is 'within normal range' or the leuteinizing hormone level is very high to start.

What happens if a man takes exogenous testosterone?

• About 2/3 of males will have complete absence of sperm in the ejaculate at 6 months

• Average time to azospermia is about 4 months.

• About 85% of males will rebound to levels > 20 million/mL by 4 months BUT only half will be at baseline by 7 months.

• Longer durations of use are associated with a longer time to recover sperm production.

Medications to Increase the Body’s Own Production of Testosterone

The following medications can indirectly increase the levels of testosterone. Note that all of these medications are used 'off-label' and require subspecialty expertise for prescribing and monitoring.

Selective estrogen receptor modulators (SERMs, also known as estrogen receptor antagonists) such as Clomiphen or Tamoxifen have been used extensively for male infertility. They stimulate the production of FSH and LH which in tern increase sperm and testosterone production, respectively. In select circumstances, they have been demonstrated to increase the probability of pregnancy (on average 2.5 x increased chance) and sperm concentration (on average 5-10 million sperm/ml) with 3-12 months of use. This works out to an increase in 1 pregnancy every 6-12 months for every 10 patients treated. (Excellent review in Chua et al. Andrology 2013, 1, 749-757) 

Patients who are most likely to derive benefit include those who have:

1. Infertility - failure to conceive for about 1 year

2. Low sperm concentration (less then about 10-20 million/mL)

3. Gonadotropin levels (FSH/LH) that are NOT excessively high (the medications work by increasing FSH and LH - if they are already high, making them higher usually will not help)

Coastal Care Pharmacy: 104-5795 176 Street, Surrey BC V3S 4E1; phone 604-283-9002; fax: 778-547-6250

Prolactin 

Prolactin is a hormone released by the pituitary gland. In females it is responsible for lactation - milk production. There is no known function in males. The units of measurement are usually in microgram per litre (ug/L, the same as nanograms/mL = ng/mL); sometimes, prolactin may be reported in milli-International Units per litre (mIU/L). Prolactin 1 ug/L is roughly equal to 20 mIU/L). The normal range is generally less than about 20 ug/L (about 400 mIU/L). 

Prolactin is measured in males because men with infertility have a higher risk of having an issue with pituitary dysfunction, especially 'prolactinomas'. These are tumors that grow in the pituitary gland and can affect infertility and sexual function, among other things. Minor elevations are causeed by a very large number of benign conditions - things such as exercise, sexual intercourse, stress and marijuana can all cause prolactin to be increased. Serious causes, such as prolactinomas, are very uncommon with levels of prolactin less than 100 ug/L. 'Micro'prolactinomas (tumors less than 1 cm in size) may be seen with levels of between 100-250 ug/L (virtually never with levels less than 50 ug/L) and 'Macro'prolactinomas (tumors over 1 cm in size) are usually not seen unless levels are over 250 ng/mL.

Evaluation of an elevated prolactin will generally include:

1. Repeat Prolactin

2. TSH

3. Creatinine

4. Liver function tests

5. Other: GH, IGF, fasting morning cortisol, ACTH, LH, FSH, testosterone - an Endocrinologist is usually consulted

6. MRI of the sella turcica

Fortunately, prolactin secreting tumors are rarely cancerous and usually amenable to treatment with medication. Bromocriptine (dose titrated from about 1 mg/day up to 30 mg/day in 1 mg/day increments) or Cabergoline (0.25-0.5 mg/week or twice weekly and increased until prolatin levels are normalized) are the 2 primary medical treatments. Surgery is sometimes indictated for large tumors or one wished to avoid life-long medication treatment.

Estradiol

Estradiol is the primary female sex hormone. It is, however, also produced in males and has a number of important functions in males - including bone strength and absorption of fluid in the rete testis. What is also interesting is that the brain indirectly detects testosterone levels by estrogen levels - and reducing estrogen levels may stimulate the production of leutenizing hormone - and consequently the testicular production of testosterone.

Most estradiol is produced by the 'aromatization' of testosterone to estradiol - this occurs in several types of cells but most importantly in the Leydig cells of the testis and (probably to a much lesser degree) by fat tissue. The role of estradiol in male fertility is important but not well understood. Therefore, read the following discussion with that in mind.

The balance between testosterone and estradiol levels is thought to be important in men. This balance is sometimes described as the 'Testsoterone:Estradiol or T:E ratio'. Some have proposed that a relative excess of estradiol to testosterone can impair sperm production. A T:E ratio of greater than 10:1 has been proposed as normal (using T in ng/dL and estradiol as pg/mL).

Ratios only work when the units are consistent. Confusing things is the fact that countries use different units of measurement for T and E. As a result, the 'ratio of greater than 10:1' reported by studies coming from the the USA may not apply elsewhere if the reported units are different (see below for conversion of units). As a consequence, the 'normal' T:E ratio in Canada should be greater than about 1:10 (about 10 nmol/L of testosterone to about 100 pmol/L of estradiol). The key is that too little testosterone relative to estradiol may be an issue for sperm production.

Given that relatively high estrogen levels compared to testosterone may impair sperm production, one strategy to improve the situation is to reduce estradiol production. This is done with aromatase inhibitors. Examples:

Anastrazole 1 mg daily

Letrozole 2.5 mg daily

Studies have suggested that this approach can help improve sperm concentrations. It is critical to note that these observations have not been studied in a 'randomized controlled trial' and for treatment should be discussed with your urologist to see if a trial is appropriate. If treatment is to be longer than 3-6 months, some monitoring of liver function is advised.

Unit conversion for Testosterone and Estradiol

Estradiol levels are reported in picomoles per litre (pmol/L); this can be coverted to picogram per millilitre (pg/mL) by dividing by about 4 (3.68 to be precise). pg/mL x 3.7 = pmol/L. Note that the denominator is also frequently changed - from L to mL which confuses things even more.

Normal male estradiol levels: about 40-150 pmol/L OR 10-40 pg/mL

Testosterone levles are reported in nanomoles per litre (nmol/L); this can be converted to nanograms per decilitre (ng/dL) by multiplying by about 30. Note that the denominator is also frequently changed - from L to dL which makes things evern more confusing. Most commonly reported:

Normal male levels: 10-30 nmol/L = 300-1000 ng/dL

Hypogonadotropic Hypogonadism

For idiopathic causes (for example, Kallman's Syndrome), spermatogenesis can often be induced by administration of gonadotropins.

There are multiple regimens to 'jump start' testosterone production and sperm production (spermatogenesis). The fundamental approach is to stimulate testosterone production by administration of leuteinizing hormone (LH or similar substances such as hCG) which may be sufficient in some cases. Not uncommonly, some follicle stimulating hormone is required (FSH or similar substances such as hMG). Response takes a minimum of 3 months and typically 6-9 months - in some cases it may take up to 2 years.

This sort of approach is successful in about 90% of men, though it is uncommon for very high concentrations of sperm to be produced (most men will have concentrations of sperm less than 70%). In many cases, the addition of in vitro fertilization is required.

Successful restoration of sperm production is more likely when the testes are larger, when a man has been on gonadotropins in the past (e.g. hCG, hMG, LH, FSH - the testis is already 'primed), and when the testes have are fully descended in the testis (i.e. did not have undescended testis/cryptorchidism).

There are several different regimens. One approach is:

1. hCG 2000 units three times per week (on the same day) intramuscular to the thigh. hCG vial contains 10,000 units of hCG powder dissoving with 5 mL yeilds 2000 units/mL. Patient is to inject 1 mL of this concentration.

   1. Notes: Dose may be reduced to 1500 units; functionally works similarly to LH which induces testosterone production by the testes.

   2. Pregynl 10,000 units

2. HMG 75 units (the contents of one vial) three times per week can be added if the sperm concentration has not risen above 5-10 million/mL after 6 months; it can be added to the same syringe used to inject the hCG

   1. Notes: dose may be reduced to 37.5 units. Also konwn as menotropin or human menopausal gonaddotropin. HMG is mixture of FSH and LH, sometimes with some hCG. In some cases, recombinant FSH may be used alone. Trade names include Repronex, Pergonal, Menopur which all have LH and FSH in equal amounts

   2. Menopur or Repronex 75 units three times per week