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REPRODUCTIVE BIOLOGY: ON FOLLICLE-STIMULATING HORMONE

The following points are made by James A. Dias (Nature 2005 433:203):

1) Each year, approximately 20% of couples in the US consult a fertility specialist because of problems with infertility. Many will seek help through assisted reproductive technologies[1]. As part of such treatments, women may receive courses of follicle-stimulating hormone (FSH) to stimulate the recruitment and maturation of many ovarian follicles. At present, however, the hormone must be injected -- a difficult and time-consuming process. Although the nature of FSH and other glycoprotein hormones has been known for more than 30 years, there is still no orally active therapeutic drug.

2) But such a drug might one day be developed, thanks to recent work[2]. Researchers have determined the three-dimensional structure of FSH bound to the large extracellular region of its receptor (FSHRHB). Their work could lead to the development of small molecules with the same effects as FSH (agonists). It also opens up the possibility of developing non-steroidal FSH antagonists, for use as contraceptives in men to block sperm production, and in women to block oocyte development. On a more fundamental level, FSHR is part of the family of horseshoe-shaped leucine-rich-repeat proteins -- named for a repeated motif that always contains leucine amino acids -- and is the latest member of this family to have its structure determined[3]. It is also among the largest of the G-protein-coupled receptors (GPCRs), proteins that constitute roughly 30% of drug targets[4], and so its structure sheds light on their mechanism of action, too.

3) Unlike many GPCR ligands, FSH is a highly complex molecule, and it has been studied exhaustively[5]. It is composed of two different subunits, alpha and beta, each of which is decorated with two long chains of carbohydrate. FSH shares an identical alpha-subunit with three other glycoprotein hormones: luteinizing hormone, which induces testosterone production in males and the final maturation of oocytes and subsequent ovulation in females; thyroid-stimulating hormone, which regulates thyroid function; and chorionic gonadotropin, which signals pregnancy. FSH itself stimulates the initial maturation of ovarian follicles, and supports sperm production.

4) Given the shared alpha-subunit, the basis for the specificity of action of these hormones has been a mystery, in which the dissimilar beta-subunits are intuitively implicated. Without this specificity, when chorionic gonadotropin, for instance, reaches the high concentrations that it does during pregnancy, other tissues would be inappropriately -- even disastrously --overstimulated. For example, ovarian hyperstimulation, a potentially life-threatening syndrome, has been associated with mutations in FSHR that bypass the specificity controls, allowing this receptor to bind to chorionic gonadotropin.

5) The mystery is now solved by the structure of the FSH-FSHRHB complex[2]. The structure shows that both hormone subunits are involved in determining the specificity of binding to the appropriate receptor, but that both charge and stereochemistry dictate specificity, with a role for alpha-subunit amino acids primarily in the stereochemical attributes . Given the similar compositions of glycoprotein hormones, the mode of receptor binding is likely to be very similar for all of them, and so the structure of the FSH-FSHRHB complex has broad impact.

References (abridged):

1. Wright, V. C., Schieve, L. A., Reynolds, M. A., Jeng, G. & Kissin, D. MMWR Surveill. Summ. 53, 1-20 (2004)

2. Fan, Q. R. & Hendrickson, W. A. Nature 433, 269-277 (2005)

3. Kobe, B. & Kajava, A. V. Curr. Opin. Struct. Biol. 11, 725-732 (2001)

4. Hopkins, A. L. & Groom, C. R. Nature Rev. Drug Discov. 1, 727-730 (2002)

5. Dias, J. A. et al. in Vitamins and Hormones (ed. Litwack, G.) 249-322 (Academic, New York, 2002)

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PUBLIC HEALTH: FALLING BIRTHRATES AND BIOLOGICAL FERTILITY

The following points are made by Declan Butler (Nature 2004 432:38):

1) If current trends continue, Japan will be deserted by the middle of the next millennium. Japan's birth rate is so low that its population will peak in 2006 and decline thereafter(1) --raising the prospect of economic chaos as a greying population overwhelms its pension and healthcare systems. A similar situation exists in South Korea, Italy, Spain, and across most of Eastern Europe. In only four industrialized countries are women, on average, having the two children needed to sustain the population(2).

2) This demographic change is mostly the result of a social climate in which couples are choosing to have fewer children, or none at all. But might something more sinister be going on, such as environmental pollution or sexually transmitted diseases causing a decline in male or female fertility?

3) What is alarming is that few credible data have been collected on the issue. If our biological fertility is on the slide, it is happening against a background of scant interest from research organizations. But there are reasons to be concerned. For one thing, women's fertility declines with age -- and this means that the trend to start families later is bound to create problems. Looking ahead, the expansion of in vitro fertilization may create a cohort of adults who have inherited their parents' fertility problems.

4) The shift towards having more sexual partners in a lifetime carries another infertility risk: sexually transmitted diseases. Some 5% of Americans of reproductive age are infected with the bacterium Chlamydia trachomatis, a major cause of female infertility -- which is rarely diagnosed as it produces no obvious symptoms(3).

5) Fertility experts are also concerned that another epidemic --of obesity -- may bring infertility. Many severely obese women fail to ovulate, even if they report regular menstrual cycles. And obesity is linked to polycystic ovary syndrome, an important cause of infertility in which ovarian follicles fail to mature. Up to 10% of US women are thought to have this condition; it is difficult to be certain of the figure because of disagreements about diagnosis(4).

6) Smoking, alcohol consumption, and a range of other lifestyle factors can all reduce a couple's ability to conceive, usually affecting women more severely than men. Most of these factors act through hormonal pathways, so understanding these interactions poses a major challenge to endocrinologists.

7) But one of researchers' biggest obstacles is that our fertility is mainly determined by the environment we inhabited in the womb(5). A woman's stock of eggs is defined by the number and maturity of her ovarian follicles when she herself was an embryo. Normal fetal follicular development depends on the mother's diet and other lifestyle factors, including her exposure to chemicals. Adult male sperm count and quality is determined largely by the development of sperm-nurturing Sertoli cells in the embryonic testes. This depends heavily on exposure to sex hormones in the womb, which again is influenced by the mother's lifestyle and other environmental factors.

References (abridged):

1. Statistical Handbook of Japan 2004 (Statistics Bureau, MPHPT, Tokyo, 2004)

2. World Fertility Report: 2003 (UN Department of Economic and Social Affairs, Population Division, New York, 2004)

3. Miller, W. C. et al. J. Am. Med. Assoc. 291, 2229-2236 (2004)

4. Azziz, R. Reprod. Biomed. Online 8, 644-648 (2004)

5. Sharpe, R. M. & Franks, S. Nature Cell Biol. 4 (Suppl. 1), S33-S40 (2002)

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PUBLIC HEALTH: ENVIRONMENTAL POLLUTION AND MALE FERTILITY

The following points are made by R.J. Aitken et al (Nature 2004 432:48):

1) During the past 50 years, the rapid expansion of the chemicals industry in both the developed and developing worlds has resulted in the release of a plethora of xenobiotics (molecules foreign to biological systems) into the environment[1,2]. These alien molecules have worked their way into our lives in a variety of forms, including pesticides, herbicides, cosmetics, preservatives, cleaning materials, municipal and private waste, pharmaceuticals, and industrial by-products. Awareness of the biological risks of chemical toxicity has increased considerably in recent years, but some of these chemicals have long half-lives and have been detected in environmental samples 10-20 years after they were banned for sale or use.

2) Analysis of the biological fallout from environmental pollution has generally centered on the risks for induction of certain kinds of cancer. But it is becoming increasingly apparent that another major target of this chemical barrage is the reproductive system, particularly in the male[2]. This was first recognized more than 30 years ago, when male workers exposed to 1,2-dibromo-3-chloropropane, an agricultural control agent used to kill nematodes, exhibited severe disruption of sperm development and infertility[3]. Since then, numerous independent studies[4] have associated occupational exposure to pesticides, herbicides, industrial agents and heavy metals with poor semen quality and impaired fertility. Although male reproduction can be affected by a variety of mechanisms that affect hormone balance and other metabolic systems, the disruption of germ-cell differentiation and sperm quality seems to involve two fundamentally different routes of exposure.

3) Xenobiotics and other environmental factors such as radiation can act directly on male germ cells within the mature testis. The highly effective proofreading and repair of DNA in the stem cells that produce sperm means that the male germ line has one of the lowest spontaneous mutation rates in the body[5]. But as these cells go through meiosis, the cell-division process that produces reproductive gametes, their capacity for DNA repair is reduced and their ability to respond to such damage by undergoing programmed cell death is progressively lost. Moreover, once they are released from the tissue that produces them, the germinal epithelium, male germ cells can no longer rely on the protection previously afforded by their nurse cells in the testes, the Sertoli cells.

4) Thus, as soon as sperm are released from the germinal epithelium, they are on their own. Bereft of the cytoplasm that houses protective enzymes such as catalase or superoxide dismutase in somatic (non-germ) cells, sperm are committed to a sojourn of about a week in the epididymis, the duct system in which they are remodelled in preparation for ejaculation. Subsequently, they must spend up to six days swimming around the female reproductive tract searching for an egg. During this long and perilous marathon, sperm are particularly vulnerable to DNA damage by a variety of environmental factors. All in all, the sperm is much more susceptible to damage than the egg because of its prolonged solitary existence and relative lack of protective, repair and self-destruct mechanisms.

5) The second route by which xenobiotics exert an influence on male reproduction is less direct, through exposure of women during pregnancy and subsequent disruption of reproductive tract development in male embryos. Such action is thought to affect both the germ cells and the somatic tissues of the male tract, and the consequences include a complex array of pathological changes collectively known as the "testicular dysgenesis syndrome", or TDS, in the offspring. The features of TDS include poor semen quality, hypospadias (defective development of the urinary tract), testicular cancer, and cryptorchidism (the failure of one or both testes to descend).

References (abridged):

1. Robaire, B. & Hales, B. F. Advances in Male Mediated Developmental Toxicity (Kluwer/Plenum, New York, 2003)

2. Klaassen, C. D. Casarett & Doull's Toxicology: The Basic Science of Poisons, 6th edn (McGraw-Hill, New York, 2001)

3. Whorton, D., Milby, T. H., Krauss, R. M. & Stubbs, H. A. J. Occup. Med. 21, 161-166 (1979)

4. Oliva, A., Spira, A. & Multigner, L. Hum. Reprod. 16, 1768-1776 (2001)

5. Hill, K. A. et al. Environ. Mol. Mutagen. 43, 110-120 (2004)

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