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CNS-Hypothalamus
Case: 19 year old male with a history of minimal secondary sexual characteristic development (such as pubic hair development or an increase in the size of the testes and penis), a medical history remarkable for an inability to smell, and a semen analysis revealing azoospermia (absence of sperm in the semen).
Question:
What should be considered given this information?
Answer:
In situations where secondary sexual characteristics are not developing normally during the pubertal years, major hormonal abnormalities involving the reproductive axis are suggested.
The incomplete maturation of the male sexual organs along with an inability to smell strongly suggests an uncommon (but well described) syndrome called “Kallmann’s syndrome.” However, other causes for azoospermia need to be ruled out before this diagnosis is confirmed.
Researchers have identified a genetic basis for Kallmann’s syndrome that seems to involve a gene locus on the short arm of the X chromosome (at Xp22.3), resulting in an X linked mode of transmission (form generation to generation). Also examination of the brain and nasal regions of fetuses with Kallmann’s syndrome have identified (a) an absence of GnRH in the normal hypothalamic region of the brain and (b) clumps of GnRH neurons in the region of the medial olfactory placode (from which both GnRH neurons and olfactory neurons appear to migrate during early embryonic development to their final normal locations in the brain). This anatomic evidence suggests that both the GnRH neurons (which are required for normal hypothalamic function in the reproductive system) and the olfactory neurons (which are required to develop the ability to smell) fail to migrate (move) to their normal locations, resulting in azoospermia and an inability to smell.
In these situations, donor sperm may be required to achieve a pregnancy. However, GnRH is available commercially and it is possible to try to replace this hormone to determine whether the man will progress through puberty and begin to produce mature sperm.
Case: 32 year old male with a history of proven fertility (two children 5 and 7 years ago), an unremarkable medical history, and a semen analysis revealing oligospermia (a reduction in the concentration of sperm) with concentrations ranging between 8 and 15 million sperm per mL, 70% motile, and 40% normal forms by World Health Organization criteria. Of interest, the man describes an extremely stressful job environment that often keeps him awake at night and appears to make him “tense” continuously.
Question:
What should be considered given this information?
Answer:
Isolated mild oligospermia may be associated with many different problems. The treatment alternatives for a mild male factor include intrauterine inseminations (possibly with controlled ovarian hyperstimulation if natural cycle inseminations are ineffective) and assisted fertilization (ICSI). Since ICSI requires the couple to complete a cycle of In Vitro Fertilization this treatment option is often delayed until all other reasonable options have been exhausted.
Stress can affect sperm production. The stress is thought to alter (throw off) hypothalamic GnRH such that pituitary release of FSH and LH is also abnormal. These abnormalities subsequently lead to a sperm production abnormality.
Sperm production takes about 3 months to complete. Therefore when a man such as this quits his stressful job and relaxes, it would be expected that an improvement in sperm quality would not occur for at least 3-4 months. I personally have a difficult time strongly recommending a career change for a man if the sole issue of concern is a mild male factor. These mild male factors can often be treated effectively with simple procedures such as intrauterine inseminations. On the other hand, if the man independently decides that he is not happy with his job and wants to change employment for other reasons, then I would generally suggest a followup semen analysis a few months later to see whether the sperm quality has improved.
Case: 38 year old male with a history of unproven fertility, an unremarkable medical history, and a semen analysis revealing oligospermia (a reduction in the concentration of sperm) with concentrations ranging between 6 and18 million sperm per mL, 60% motile, and 50% normal forms by World Health Organization criteria. The FSH, LH and testosterone concentrations were assessed and they were all suppressed (reduced).
Question:
What should be considered given this information?
Answer:
If the circulating concentrations of FSH, LH and testosterone are all low then one should consider a structural lesion in the vicinity of the pituitary gland or hypothalamus that has resulted in an abnormal communication between these two components of the reproductive axis. In other words, a mass (tumor) may interfere with (block) the blood vessels between the hypothalamus and the pituitary gland such that GnRH released from the hypothalamus does not effectively cause a release of FSH and LH from the pituitary gland.
If FSH and LH are suppressed, then testicular function will also be suppressed. This means that LH will not act normally on the Leydig cells to produce testosterone and the reduced testosterone and reduced FSH will result in less sperm production.
A radiologic study of the brain should be performed in these situations. Identification of a brain tumor (or other structural lesion) would also allow for earlier treatment if necessary. An MRI provides an excellent image but can be expensive.
Case: 26 year old male with a history of proven fertility (one child 7 years ago within this marriage), an unremarkable medical history, and a semen analysis revealing severe oligospermia (a reduction in the concentration of sperm) with concentrations ranging between 3 and 5 million sperm per mL, 50% motile, and 50% normal forms by World Health Organization criteria. There is a personal history of persistent cocaine and marijuana abuse for this man over the past 4 years.
Question:
What should be considered given this information?
Answer:
The man described in this example has a history of proven fertility (he has fathered a child) and this couple has a history of reproductive success 7 years ago.
The history of recent illicit drug abuse (over the past few years) appears to be the major variable that has changed in this relationship (with respect to reproductive potential). It is known that any “mind altering” medication may affect the ability of the reproductive system to function properly, since both the male and the female gamete (sperm and egg) production is highly dependent on a delicate system of communication that involves the brain. The “mind altering” drugs appear to alter the ability of the brain’s normal messengers (neurotransmitters, etc) to work properly. The ability of the brain to orchestrate the precisely regulated reproductive system also appears to depend on many of these same messengers, which may not be working properly during exposure to illicit drugs.
The semen analysis reveals an isolated but marked reduction in sperm concentration (compared to normal). This would suggest difficulty with sperm production within the testes. Although it is possible that this man had a similar sperm quality when he previously achieved a pregnancy, it seems more likely that an event (like initiation of drug abuse or development of a varicocele) has led to this abnormality.
Ideally, the man would abandon the drug abuse and then the quality of the sperm could be reassessed a few months later. A varicocele should be identified or ruled out on physical exam. If the abnormality in semen analysis persists, then intrauterine insemination (with or without concurrent controlled ovarian hyperstimulation) or assisted fertilization may be required to treat the male factor. If the drug abuse continues, the physician will also need to make an ethical decision regarding assisting in reproduction in this context.
Case: 31 year old male with a history of unproven fertility, a medical history of depression being treated with a selective serotonin reuptake inhibitor (such as fluoxetine = prozac), and a semen analysis revealing a mild oligospermia (a reduction in the concentration of sperm) with concentrations ranging between 16 and 19 million sperm per mL, 70% motile, and 60% normal forms by World Health Organization criteria.
Question:
What should be considered given this information?
Answer:
The semen analysis suggests a possible mild male factor. The treatment options for a mild male factor range from natural (spontaneous) cycle intrauterine inseminations (IUIs) to controlled ovarian hyperstimulation (using FSH containing menotropins to mature multiple eggs per cycle) with IUI to In Vitro Fertilization with assisted fertilization (ICSI).
The effect of antidepressant medication on sperm quality has not been adequately described (to my knowledge) in the medical literature. In theory, “mind altering” medications (even if taken for an appropriate medical reason) may affect sperm quality. In general, if there is a good reason to take a medication (it has a known benefit) and it has minimal or no known risk then the medication should be continued.
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