Male germ cell transplantation: present achievements and future prospects.

Germ cells are unique, since their surviving descendants can undergo meiosis and differentiate into gametes, which transmit genetic material from one generation to another. We now know that male germ cells, whether they be primordial germ cells in gonadal ridges, gonocytes, or stem spermatogonia, are transplantable. The donor cells can be transferred by direct microinjection into the seminiferous tubules, rete testis or efferent ducts, depending on the recipient species. Following transplantation, the donor cells undergo spermatogenesis in the host's seminiferous tubules in rats and mice, and have even sired offspring in mice. Interspecific germ cell transfer is possible if the recipient's immune system is defective; nude or SCID mice can even produce rat spermatozoa. However, the major obstacle restricting widespread use of this new technology is its extremely low success rate. This article discusses some ideas for improving the success rate of the transfer technique, and considers several potential applications.

Condoms for the prevention of HIV transmission: cultural dimensions.

PIP: Humans being fundamentally polygamous, condoms should be recognized and promoted as central to an integrated approach for family planning, HIV prevention, and the control of sexually transmitted diseases. They must be more widely and effectively distributed and promoted in both more developed and developing nations. Available data on the ability of condoms to stem the transmission of HIV are limited, yet nonetheless indicative of condoms' general protective effect. Comparatively high prevalence and use of condoms are, however, found only in Japan, Sweden, Finland, Denmark, Singapore, and Trinidad and Tobago. Use in the U.S. is under that of a generation ago, while only extremely low levels are found throughout most of Africa, Asia, and South America. The industrialized nations of the West are most readily in the position of affording increased condom prevalence and use through increased manufacturing capacity and intensified promotion of moderate behavioral change among users. The nations of the 3rd World, however, lack the monetary and logistical resources to finance a rapid increase in condom prevalence, and are demanded to focus their energies more than ever where they are most needed, and expected to produce most significant impact. Up to $1 billion/year would be needed from donor agencies to meet universal need for condoms in Africa alone. Simple and cheap though condoms may be, such cost is too high to bear. The use of social marketing is therefore endorsed to target high-risk groups of populations as a means of maximizing resources for greatest potential impact. NGOs will play a major role in condom distribution, and should expect to work with, instead of through, ministries of health.^ieng

Absence of hCG-like activity in the blood of women fitted with intra-uterine contraceptive devices.

Blood was obtained at various stages of the menstrual cycle from 201 women fitted with intra-uterine contraceptive devices (IUDs), and plasma levels of hCG were determined by radioimmunoassay. Urine samples were obtained from 117 of these women and tested, before and after sephadex gel filtration, in a haemagglutination inhibition test for pregnancy (Pregnosticon). Plasma hCG was undetectable (less than 25 MLU/ml) in all but one of the 201 women and, in this instance, the hCG-assay appeared to be measuring a midcycle peak of LH, as evidenced by high plasma FSH levels. All unextracted urines gave negative results in the Pregnosticon test but, after extraction, 18 of the 117 urines gave positive reactions, most of these being from women at midcycle or in the luteal phase. We conclude that the IUD does not permit the development of the embryo to a point where it is capable of secreting measurable amounts of hCG. Recent claims to the contrary are probably due to cross-reaction of LH or non-specific interference in the assays used for measuring hCG.

Hybridizing Old and New World camelids: Camelus dromedarius x Lama guanicoe.

Thirty female dromedary camels were inseminated on a total of 50 occasions with 2-4 ml of fresh guanaco semen diluted with an equal volume of commercially available camel semen extender. Similarly, nine female guanacos were inseminated on 34 occasions with 4-6 ml of fresh, diluted camel semen. Only two of the dromedary females conceived; one aborted a female foetus on day 260 of gestation and the other gave birth to a stillborn female calf on day 365. Six conceptions occurred in the female guanacos. Two of these conceptuses, diagnosed by ultrasound, were resorbed between days 25 and 40 of gestation, one female foetus was aborted on day 291, another female foetus was aborted on day 302, and one female calf was stillborn on day 365 of gestation. The sixth foetus, a male, was born prematurely but alive after a 328-day gestation. It had a phenotypic appearance intermediate between that of a camel and a guanaco and its hybrid parentage was confirmed by the DNA fingerprinting of eight llama microsatellites. To our knowledge, this is the first viable hybrid ever to be produced between Old World and New World camelids, which have been reproductively isolated from one another for at least 11 million years. The preponderance of female hybrids is in accordance with Haldane's law. Histological examination of their ovaries revealed a failure of meiosis, with only an occasional abnormal oocyte surrounded by follicle cells. Although the diploid chromosone number of camels and guanacos is the same (2n = 74), sufficient genetic change has taken place to make the pairing of homologous chromosomes no longer possible.

Salivary oestriol and progesterone concentrations in women during late pregnancy, parturition and the puerperium.

Oestriol and progesterone concentrations were measured by specific radioimmunoassays in the saliva of six women on a daily basis during the last month of pregnancy, at frequent intervals during labour and daily during the puerperium. Salivary steroid concentrations are thought to reflect the circulating concentrations of the free hormone, and hence may be more biologically relevant than the total plasma concentration, or the urinary excretion of a metabolite. There was no sign of a fall in salivary oestriol or progesterone concentrations before the onset of labour. During the first and second stages, the concentrations fluctuated widely, perhaps due to alterations in uterine blood flow. After delivery of the placenta, hormone concentrations declined abruptly. Oestriol reached undetectable levels of less than 0.1 nmol/l within a day, whereas progesterone concentrations declined somewhat more slowly, approaching follicular-phase values after 2-3 days. This slower decline in the concentration of progesterone may be due to a leaching-out of the hormone from body fat stores. The absence of any prepartum progesterone withdrawal presumably explains the characteristic postpartum delay in the onset of lactogenesis.

Ovulation in prenatally androgenized ewes.

The ovarian activity of prenatally androgenized ewes was studied by measuring plasma progesterone concentrations in daily samples of peripheral blood, and by examining the ovaries at laparotomy. Ewes that were exposed to testosterone between days 30 and 80, 50 and 100 or 70 and 120 of foetal life by implanting their mothers with 1 g testosterone, failed to show regular overt oestrous cycles, although some of them ovulated, whereas ewes exposed to testosterone between days 90 and 140 of foetal life had normal oestrous cycles. The incidence of ovulatory failure appeared to increase with age in ewes treated between days 50 and 100 or days 70 and 120 of foetal life.

PIP: The effect of prenatal androgenization of ovulation in ewes was investigated by measurement of plasma progesterone concentrations and examination of the ovaries at laparotomy. The animals were exposed to testosterone by implantation of their mothers with 1 gm testosterone between Days 30-80, 50-100, 70-120, or 90-140 of fetal life. Ewes exposed during the first 3 periods to testosterone failed to show regular, overt estrous cycles, though ovulation did occur in some cases. Animals exposed between Days 90-140 of fetal life had normal estrous cycles. There appeared to be an age-related increase in the incidence of ovulatory failure in ewes exposed between Days 50-100 or Days 70-120 of fetal life.

Different fate of primordial germ cells and gonocytes following transplantation.

We have previously demonstrated that both donor primordial germ cells (PGCs) and gonocytes are capable of establishing spermatogenesis in the lumen of the seminiferous tubules of an adult host following transplantation in rats. Here we show that the PGCs, either in crude suspensions or after purification, undergo spermatogenesis only in the intraluminal compartment of the host's seminiferous tubules, while 4-5 days postpartum gonocytes also interdigitate with the host's seminiferous epithelium. The donor seminiferous epithelium was always in synchrony with the cycles of the host's spermatogenesis. It seems that the pattern of spermatogenesis of donor germ cells following transplantation in terms of its spacial location and the connection with the host's seminiferous epithelium depends on their developmental stages at transfer.

The resumption of ovulation and menstruation in a well-nourished population of women breastfeeding for an extended period of time.

We have studied a large group of Australian women breastfeeding for an extended period of time to determine the duration of lactational anovulation (n = 89) and amenorrhea (n = 101). Salivary progesterone assays were used to determine ovulation. These women had a mean of 322 days of anovulation and 289 days amenorrhea. Less than 20% had ovulated and less than 25% had menstruated by 6 months postpartum. The latest ovulation was at 750 days and the latest menstruation at 698 days. There was no significant correlation between any measure of maternal nutritional status and the duration of anovulation or amenorrhea. Neither the time of first supplement introduction to the baby nor the amount of supplement given was an accurate predictor of the return of ovulation or menstruation. However, our results clearly show that lactational amenorrhea can provide good protection against pregnancy in the 1st 6 months postpartum, even in well-nourished women who are giving their babies supplemental feeds.

PIP: The authors studied a large group of Australian women who breastfed for a long period of time to determine the duration of lactational anovulation (n=89) and amenorrhea (n=101). Salivary progesterone assays were used to determine ovulation. These women has a mean of 322 days of anovulation and 289 of amenorrhea. Less than 20% had ovulated and 25% had menstruated by 6 months postpartum. The latest ovulation was at 750 days and the latest menstruation at 698 days. There was no significant correlation between any measure of maternal nutritional status and the duration of anovulation or amenorrhea. Neither the time of 1st supplement introduction to the baby nor the amount of supplement given was an accurate predictor of the return of ovulation or menstruation. However, these results show clearly that lactational amenorrhea can provide good protection against pregnancy in the 1st 6 months postpartum, even among well-nourished women who are providing their babies with supplement feeds.

Functional analysis of the cooled rat testis.

Direct cooling of the testis results in the depletion of most germ cells in vivo. Germ cell-depleted testes are now commonly used to investigate spermatogenic regeneration and can serve as recipients for germ cell transplantation. The present study explored the effects of cooling rat testes on the depletion of endogenous germ cells, spermatogenic regeneration, and Sertoli cell function. Adult rat testes were cooled with iced Ringer's solution for 60 minutes, which results in the initiation of apoptotic germ cell loss within 8 hours. Pachytene spermatocytes at stages XII-I were the cells most sensitive to cooling. In 46%-67% of seminiferous tubule cross-sections, only Sertoli cells remained in the cooled testes 3-10 weeks after treatment. Germ cell loss was accompanied by a significant decrease in circulating inhibin B and an increase in follicle-stimulating hormone concentrations, which indicated a change in Sertoli cell function. Quantitative analysis of mRNA expression associated with apoptotic signals showed no significant uniform changes among the cooled testes, although some individuals had a distinct up-regulation of FAS mRNA at 24 hours. Attempts to use the cooled testes as recipient testes for mouse-to-rat germ cell transplantation were undertaken, but none of the mouse germ cells transplanted into the testes 15-34 days after cooling appeared to have undergone spermatogenesis 64-92 days after transplantation. These data suggest that modifications to Sertoli cell function resulting from testicular cooling create an environment that is unable to support spermatogenesis by donor germ cells.

Synchronization of mammalian circadian rhythms by melatonin.

While pinealectomy (Px) has little effect on mammalian circadian rhythms, daily injections of the pineal hormone melatonin in rats have profound effects. These can be classified according to their effects under three categories of desynchronization: external desynchronization, internal desynchronization and phase-shift of the zeitgeber (Aschoff, 1969). Externally desynchronized rats, free-running in constant darkness (DD), can be entrained to a 24-hour regime of melatonin injection. Entrainment depends upon the suprachiasmatic nuclei (SCN) since lesions to the SCN prevent it. Although no animal model for internal desynchronization exists, rats whose circadian rhythms are disrupted or arrhythmic in constant light (LL) are synchronized by daily melatonin injection, and the rate and direction of responses to phase-shift of the zeitgeber can be altered with daily melatonin administration. These and other results suggest melatonin may be useful therapeutically for such human desynchronizations as jet-lag and shiftwork, and preliminary data using human subjects are presented.

Sexual differentiation of the urogenital system of the fetal and neonatal tammar wallaby, Macropus eugenii.

In male tammar wallabies, the scrotum is the first organ to become sexually differentiated, 4-5 days before birth (day 22 of gestation). This is followed by enlargement of the gubernaculum and processus vaginalis one day before birth. However the indifferent gonad does not show any signs of testicular cord formation or androgen production until later, at around the time of birth; this is more pronounced at 2 days post-partum (p.p.), when the testis takes on a characteristic rounded appearance. Primordial germ cells proliferate throughout the testis at this time, although the testis does not become significantly heavier than the ovary until around 80 days p.p.. In females, the appearance of the mammary glands is the first sign of sexual differentiation 4-5 days before birth. The indifferent gonad first shows signs of developing an ovarian cortex and medulla 7 days after birth. The migrating germ cells are confined to the cortex, and first start to enter meiosis about 25 days after birth. The Wolffian (mesonephric) ducts are patent to the urogenital sinus in fetuses at day 21 of gestation. In the female they have started to regress by 10 days p.p. and only rudiments remain by day 25 p.p.. The Müllerian (paramesonephric) ducts develop adjacent to the cranial pole of the mesonephros at about day 25 of gestation and grow caudally to meet the urogenital sinus between days 2 and 7 p.p.. The Müllerian duct of the female develops a prominent ostium abdominale by day 9 p.p., but this structure has completely regressed in males by day 13 p.p.. The testis and ovary both migrate caudally, together with the adjacent mesonephros, at about day 10 p.p.. The ovaries remain around the level of lumbar vertebra 4 after about day 7 p.p., while the testes continue to descend. The testes enter the internal inguinal ring at about day 25 p.p., about the time that prostatic buds first appear in the urogenital sinus, and are in the inguinal canal from days 25 to 36 p.p.. They enter the scrotum at around day 36 p.p., and testicular descent is complete by days 65-72 p.p.. Melanin develops in the tunica vaginalis 72 days after birth. The overall development of the urogenital system in this marsupial is similar to that of eutherians but the sequence of events differs, with some aspects of genital differentiation preceding gonadal differentiation, apparently because they are directly controlled by X-linked genes, rather than indirectly controlled by gonadal steroids.

Premature introduction of progestin-only contraceptive methods during lactation.

Experts on contraceptive technology concur that progestin-only methods can be used safely during lactation. However, very few studies exist of the effects on lactation of the introduction of progestin-only methods prior to the sixth postpartum week. Since progesterone withdrawal is the likely stimulus that initiates lactogenesis, it appears necessary for natural progesterone levels to decline to baseline before a progestin-only contraceptive is initiated. Therefore, the use of such contraceptive methods should be delayed for at least 3 days after the birth. Non-hormonal methods remain the first choice category of contraceptive methods for breastfeeding women, since there is no possibility that they will interfere with lactation. Progestin-only methods comprise a viable and often desirable next choice category, although the timing of their commencement must be determined with care in order to support lactation.

PIP: All major international family planning organizations have endorsed the use of progestin-only contraceptive methods once lactation has been established. Prospective, multicenter studies of infants of acceptors of progestin-only pills, injections, and implants have found no deleterious effects of the drug on infant growth and development; however, women enrolled in these trials did not initiate method use until at least the sixth postpartum week. Of concern is a recent trend toward administration of progestin subdermal implants and injectables to women prior to their discharge from the hospital (i.e., 0-72 hours after delivery). Since progesterone withdrawal is the likely stimulus that initiates lactogenesis, natural progesterone levels need a chance to decline to baseline before progestin contraceptive use is initiated. Moreover, the immature neonatal liver may have difficulties metabolizing exogenous steroids, the binding capacity of plasma is low, and the immature kidney may be inefficient in steroid excretion. Use of progestin-only contraceptive methods should be delayed for at least 3 days (optimally, until 6 weeks) after birth so lactation can become established. Nonhormonal methods remain the first choice for breast-feeding women, given the lack of potential to interfere with lactation, while progestin-only agents are a viable second choice.

The HIV/AIDS pandemic: new ways of preventing infection in men.

Nelson Mandela has recently said that HIV/AIDS is the greatest health crisis in human history. At the end of 2001, UNAIDS estimated that there were 40 million people living with the infection, with 5 million new cases, and 3 million deaths per year. About half the infected individuals are men, and heterosexual intercourse is the commonest route of infection. Although condoms remain the first line of defence, they are unpopular in parts of Africa, where the pandemic is worst, so an alternative is needed. Post-coital penile hygiene has received little attention. Wiping the glans penis and inner foreskin immediately after intercourse with an acidic solution like lemon or lime juice, or even vinegar, should immediately kill the virus and might prevent infection; clinical trials are urgently needed. Several studies in Africa and India have now conclusively demonstrated a 2-7-fold protective effect of male circumcision against HIV infection. Circumcision removes the inner foreskin and the frenulum, which are the prime sites of HIV entry into the penis. Since male circumcision also protects men from human papilloma virus infection, and their wives from cervical carcinoma, the procedure should be encouraged in developed and developing countries.

The future fertility of mankind: effects on world population growth and migration.

The world's population, currently just over 6 billion, is projected to increase to 9-10 billion by the year 2050. Most of this growth will occur in the developing countries of Asia, where there is an enormous unmet demand for contraception, while an increasing number of developed countries will have declining populations. The human immunodeficiency virus (HIV) pandemic will target developing countries, with India destined to become its new epicenter. By 2050, there may be 1 billion HIV-infected people in the world. The significant protective effect of male circumcision may spare Islamic countries, such as Pakistan, Bangladesh, Iran and Indonesia, from the worst effects of the pandemic. Australia will be increasingly threatened by the high rates of population growth of her Asian neighbours. This, coupled with political instability and sea-level rises as a consequence of global warming, will turn the present trickle of refugees from a variety of Asian countries seeking safe haven on our sparsely populated northern coastline into a veritable flood. There will come a time when we have neither the manpower, nor the means, nor even the moral right to intercept, detain or repatriate the thousands who will come in peace, in search of a better life. However, if Australia is to stabilize its future population at around 23 million, which seems highly desirable on ecological grounds, then the net immigration rate must be limited to approximately 50000 people per year. Because the final point of departure for all these refugees is Indonesia, it is essential that Australia maintains good relations with Indonesia, so that together we can attempt to manage the refugee problem. However, Indonesia's own population is destined to increase by 100 million in the next 50 years, which will only exacerbate the situation. Australia would be well advised to make a major increase in its paltry financial assistance to Indonesia's excellent family planning programmes, which are currently starved of funds. Helping Indonesia to contain its population growth is Australia's best long-term investment for its own future.

Contraceptive effects of levonorgestrel implants in a marsupial.

The effect of subcutaneous levonorgestrel implants on reproduction in female tammar wallabies was investigated during the breeding and non-breeding season. Female tammars were given either a control or a levonorgestrel implant and their pouch young were removed to terminate embryonic diapause. Both the control and the levonorgestrel-implant animals treated during the months of May and June gave birth, demonstrating that levonorgestrel does not prevent the reactivation of the diapausing blastocyst or its subsequent development when given at these times. However, none of the levonorgestrel-treated animals mated post partum, whereas all of the control females that gave birth had a post partum oestrus and mated. Control animals gave birth again when the neonate was removed, and continued to breed normally during the following 36 months of the investigation. None of the levonorgestrel-treated animals gave birth again or mated during the next 36 months. Animals given control implants during December did not reactivate or give birth until the normal start of the breeding season in late January. Animals treated with levonorgestrel implants during December did not reactivate with the control animals at the beginning of the breeding season and did not give birth during the next 36 months. There were no effects of levonorgestrel treatment on early lactation. Levonorgestrel implants were removed from six females and four of these animals resumed reproductive activity, confirming that the contraceptive effect of the implants is reversible. Levonorgestrel implants therefore provide a highly effective, reversible and long-term method of contraception for tammar wallabies. This contraceptive system appears to offer a method of population control for the management of overabundant captive and selected wild populations of macropodid marsupials.

Assisted reproductive techniques for hybridization of camelids.

The camelid family comprises the Old World camelids (or dromedary and Bactrian camels) and the New World camelids (namely the llamas, alpacas, guanacos and vicunas). Although the species within each group can hybridize among themselves to produce fertile offspring, it is only recently that a hybrid between New and Old World camelids has been reported. To create this hybrid, semen was collected from male camels by artificial vagina (AV) and inseminated into female guanacos (n = 9) and llamas (n = 3) at the appropriate stage of their follicular wave cycle. Similarly, guanaco and llama semen was collected, also by AV, and inseminated into female camels (n = 42). Although several conceptions occurred, only one hybrid (camel sire x guanaco dam) continued to term and was born alive after 328 days of gestation, and another is pregnant at the time of writing (camel sire x llama dam). Further studies are presently being carried out using extraspecific embryo transfer to try and improve the success rate of live offspring being born. Female guanacos (n = 4) are treated with hormones to stimulate their ovaries to produce several follicles before being inseminated with camel semen. Of the 12 camel recipients that have to date received hybrid embryos (camel sire x guanaco dam), 10 conceived, but 9 of these subsequently aborted between 30 and 365 days and only one recipient was still pregnant at the time of writing.

Mammary glands in male marsupials. 2. Development of teat primordia in Didelphis virginiana and Monodelphis domestica.

Young and adults of both sexes of two didelphid marsupials, Didelphis virginiana and Monodelphis domestica, were examined externally for evidence of mammary gland development. Female young possessed teat numbers typical of adult females (13-15 in D. virginiana; 11-13 in M. domestica). Male young showed variable teat numbers which were always low compared with females, with the majority possessing 2-4 in anterior positions. Teats were also present in adult males of both species, in similar numbers and locations to those of young males. There are no previous reports of the presence of teats in any adult male marsupials. No mammary primordia in males have been recorded at any stage of development in the most thoroughly studied Australian marsupials. Our findings strengthen the view that there is a dichotomy between the two marsupial lineages in the regulation of male mammary gland expression.

Breast feeding.

PIP: At this time the fact that breastfeeding can play an important contraceptive role has become little more than a myth in the minds of many people. The change has had serious consequences for rates of population increase and for infant health, particularly in many developing nations. In developed countries breastfeeding is generally regarded as an aftermath of human reproduction. The medical profession has largely ignored the subject. The failure of physicians, scientists, theologicans, administrators, and politicians in developed countries to appreciate the full significance of breastfeeding for the spacing of births and the health of infants has had serious consequence for developing countries. The recent World Fertility Survey showed that in many developing countries young women who are educated, urban, and affluent are abandoning breastfeeding in favor of bottle feeding. The exact mechanism by which suckling inhibits fertility is not totally understood. It clearly is the suckling stimulus itself, rather than the production of milk, that is crucial. In women the sensitivity of the nipple increases markedly at the time the baby is born. The phenomenon may be important for enhancing inhibitory inputs to the brain. A reasonable hypothesis to explain the contraceptive effect of breastfeeding is that neural inputs from the nipple reach the hypothalamus. There they have the effect of stimulating the release of beta endorphin, which is thought to suppress the discharge of hypothalamic gonadotrophin releasing hormone. The result is decreased secretion of luteinizing hormone and therefore a failure of ovulation. In many countries, both developing and developed, it is common for the mother to start feeding the baby supplements early, sometimes from the day of birth. This practice diminishes the supply of breast milk, exposing the baby to an unnecessary risk of infection and undermining the contraceptive effect of breastfeeding. Another current controversy is the type of contraceptive a lactating mother should use and the time for her to start using it. In developed countries, where women usually breastfeed for a relatively short period of time and where they take for granted the availability of an almost foolproof method of contraception, the practice has been to advocate barrier methods. In developing countries the situation is totally different. The contraceptive protection afforded by lactational amenorrhea is at least as good as that of any modern contraceptive. A most effective and safe contraceptive for lactating women in developing countries and the simplest to administer is Depo-Provera. The controversy regarding the use and risks of Depo Provera are reviewed.^ieng

Effects of time zone changes on performance and physiology of airline personnel.

This study is the second of a series of experiments describing the effects of time zone changes on the performance and menstrual cycle changes in a group of 16 female airline personnel. Four groups of four subjects each spent 4 d in the isolation unit of the University of Manchester. One group acted as control; the other three groups were subjected to two 8-h retardations in time, representing Westerly flight. All groups were required to complete an identical battery of workload tasks. In addition, the effects of a therapeutic preparation (mepiprazole hydochloride) were studied in a double-blind experiment. The results of the study confirmed previous experiments in that there was impaired performance in individuals subjected to time zone changes when work was carried out in local time, but the results were difficult to compare with those obtained in Easterly shifts. The therapeutic agent appeared to have little influence on the effect of time zone changes upon subjects, although they reported favourably on its use.

The testis: the witness of the mating system, the site of mutation and the engine of desire.

There is now abundant evidence in a wide range of mammalian and non-mammalian species to show that the relative size of the testis and the morphology of the spermatozoa are infallible predictors of the mating system. Species with the largest testis/body weight ratios and the best spermatozoa have a multi-male or promiscuous mating system in which sperm competition operates. Judged by these criteria, men were not designed to be promiscuous. There is increasing evidence in humans to show that most spontaneous mutations of the germ line occur in the testis. Because these provide the variability on which natural selection can operate, the testis holds the key to evolution. Genes on the Y chromosome that control male fertility are particularly prone to mutations, perhaps because of the mutagenic metabolites produced by the metabolically active testis. Testicular descent into a scrotum, and cooling by countercurrent heat exchange between the spermatic artery and vein may have evolved as a way of holding the mutation rate in check. The hormones secreted by the testis, which control libido and aggression, ensure that these male mutations are disseminated as widely as possible throughout the population.