Martin Ritzén. bioscience explained Vol 7 No 2. Girl or boy: What guides gender development and how can this be a problem within

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1 Martin Ritzén Professor emeritus, Karolinska Institutet, Stockholm, Sweden Girl or boy: What guides gender development and how can this be a problem within sport? Introduction During the 2009 athletics world championships in Berlin, a young South African woman drew international attention when she easily took gold in the 800 metres. What was remarkable was not her winning time, but the pictures of an extremely muscular woman published worldwide with headings such as Is this a man or a woman?" Both sporting officials and the majority of journalists showed a remarkable lack of knowledge in terms of what we currently understand about normal and abnormal gender development, and how individuals come to have male or female physiology. Before we can understand deviations from normal female and male development, we need to understand the mechanisms governing sexual development during the embryonic stage, as well as during and after puberty. Normal development of the genitalia External genitalia Up to approximately 5 weeks after fertilization, male and female genitals appear identical. A small bud in the front of the groin forms the origin of the glans in boys and the clitoris in girls. A fold extending from the front of the groin and back towards the anus forms part of the body of the penis in boys and the labia minora in girls. A parallel outer fold forms the scrotum in boys, and in girls forms the labia majora. Internal genitalia In early foetal development two symmetrical paired ducts develop into respectively the male or female internal genitalia. CORRESPONDENCE Martin Ritzén; Martin.Ritzen@ki.se The male genitals the epididymis, vas deferens, seminal vesicles and prostate all develop from the so-called Wolffian ducts. The female internal genitals develop from another duct system, the so-called Müllerian ducts, which form the uterine tubes, uterus and the upper part of the vagina. The outer third of the vagina is formed from an invagination (a poach) in the area in front of the anus that becomes fused with the upper part.

2 Development of the ovaries and testicles a. The common origin of the gonads (testicles or ovaries) in male and female embryos is primarily from a primitive forebear of the kidney, whose cells form part of the gonads. During the embryonic stage, the testicles descend from their original location next to the kidneys, along the posterior abdominal wall and through the inguinal canals to their final location in the scrotum. b. In the case of ovaries, small ovarian follicles gradually develop, each of which contain a single egg cell. The ovaries remain in the abdomen, close to the inner openings of the Fallopian tubes. How genes govern development into testicles or ovaries A number of genes play a role in the development of gender. The most important is a gene on the Y- chromosome called SRY (Sex Determining Region Y). The significance of this has been demonstrated by isolating the gene and then inserting it into the cell nucleus in a fertilised mouse egg, which otherwise would have developed into a female. The result was a mouse with female chromosomes (XX), but which developed testes instead of ovaries! The testes then cause development of male outer as well as inner genitalia. In the absence of SRY in a foetus with male sex chromosomes, the child develops into a completely normal female child. Apart from the gonads, which remain undeveloped and cannot produce sex cells. Sometimes SRY sites on an X- chromosome, in which case the individual develops into a normal boy/man, despite the presence of female (XX) chromosomes. His testes cannot, however, produce sperm. The genes that govern development of ovaries are less well understood, but at least two genes are required: WNT4 and FOXL2 (see Fig 1). How hormones govern development into boys or girls Hormones governing male development When the testicles are properly developed, they begin producing the male sex hormone (testosterone) under the influence of other hormones, so-called gonadotropins. During the first three months of gestation, gonadotropin comes from the placenta, during the second and third months of gestation, from the foetal pituitary gland. Testosterone then affects embryonic development of the external genitalia so that a penis and scrotum are formed, but only after conversion of testosterone to dihydrotestosterone (DHT). If the enzyme responsible for the conversion (5- reductase) is inactive, the embryo does not develop male sexual characteristics. This results in female external genitalia. DHT works by binding the receptor molecule for male sex hormones (the androgen 2

3 receptor). A non-functioning androgen receptor results in all tissue becoming unreceptive to male sex hormones and the external genitalia also become female in such cases! Testicular Sertoli cells in the foetus produce the so-called Anti-Müllerian hormone (AMH). This inhibits the development of all organs that derive from the Müllerian ducts, i.e. the uterus and the upper part of the vagina. Testosterone, which is produced in other cells in the foetal testes, stimulates growth of the penis and scrotum (after conversion to DHT), but also inner organs that derive from the Wollfian ducts, i.e. the epididymis, vas deferens, seminal vesicles and prostate. This occurs by binding of testosterone to the androgen receptors. An XY-individual who lacks functioning androgen receptors will, in other words, lack both male and female internal genitalia, despite the foetal testes producing high quantities of testosterone! Hormones governing female development If the genetic signals for testicular development (predominantly SRY, see above) are absent, the primitive gonad (gonad = sex gland) will develop into an ovary. The genes that govern this development are not fully understood but the female development has been likened to a default pathway : In other words, if gonadal development into a testicle does not start (around the fifth gestational week), then somewhat later it will develop into an ovary. Continued development of female genitalia during the foetal stage is not hormone dependent. In contrast, female sex hormones are important for growth of the uterus, fallopian tubes, breasts and female body shape, after birth. Some growth of the external genitalia occurs, however, during the foetal stage, involving forming of the clitoris; the internal folds form the labia minora and the outer folds the labia majora. A schematic overview of the regulation of sexual development in boys and girls is shown in Fig

4 External androgens Androgen receptor (AR) DHT Male ducts Undiff. gonad SOX-9 SRY DAX1 WNT4, FOXL2 Testis Ovary AR AMH R female ducts and uterus external genitalia Figure. 1. A schematic overview of the control of sexual development during the embryonic stage. The crucial stage in the development is whether the primitive gonads develop into testicles or ovaries. Three different genes that govern male development are shown in the figure: SRY, which constitutes the most important gene for testicular development, and which requires a functioning SOX-9 gene. A gene on the X- chromosome (DAX-1) inhibits testicular development, if it is present in a duplicated or "double-dose". Once a testicle has developed it drives continued male development of the embryo: After binding to the cellular receptors for androgen hormones (AR), testosterone (following conversion to DHT) stimulates development of male external genitalia, as well as growth and development of male internal organs. The addition of androgenic ( external ) hormones to the foetus (e.g. through medication or disease in the foetus or the mother) results in masculine features in a female foetus. Anti-Müllerian hormone (AMH) from the testes inhibits development of female internal organs. If the testes do not develop, both the internal and external genitalia will be female. The female gender can be said to be the baseline. Two important genes for ovarian development have been identified to date WNT4 and FOXL2, but it is not known what other factors or hormones from the foetal ovaries are crucial for female embryonic development. Sexual development during childhood up to puberty The time from birth up to the start of puberty is a rather quiet period in terms of sexual development. The small quantities of sex hormones produced by the testicles and the ovaries are insufficient to produce the features we usually associate with puberty. Production of oestrogen by the ovaries and testosterone by the testicles only commences when the pituitary gland starts producing hormones (LH luteinizing hormone and FSH= folliclestimulating hormone) at the age of years. LH and FSH receive their name based on their effects on the ovaries, but the hormones are the same in men; whereby LH stimulates formation of testosterone and FSH the formation of sperms. 4

5 The testicles and the ovaries are not completely inactive during childhood. This is demonstrated by the fact that the physical characteristics of boys and girls already differ from the age of 6-7 years. Development of puberty At the onset of puberty, however, the increasing concentrations of testosterone and oestrogen in the blood have dramatic effects on physical development. In girls, onset of puberty is normally characterised by development of breasts, closely followed by growth of pubic hair, and the onset of menstruation a couple of years later. Onset of puberty in boys normally occurs at least one year later than girls and takes the form of growth of the testes and scrotum followed by increase in penis length and girth, growth of pubic hair, breaking of the voice, an increase in muscle-mass, and development of acne a couple of years later. All the characteristics of puberty in boys are the result of male sex hormones, primarily testosterone. In girls, the increased production of oestrogen from the ovaries causes a gradual development of the breasts and eventually the onset of menstruation. In contrast, the growth of pubic hair in the genital region and axilla, as well as acne in girls too, is an effect of the relatively moderate secretion of male sex hormones from the ovaries and adrenal glands. Male hormones are also responsible for the increased activity in some sweat glands (predominantly in the axilla), which are characteristic of both girls and boys from the onset of puberty: the children start smelling like adults. This is more noticeable in boys, since they have much higher concentrations of male sex hormones. Consequently, boys changing rooms smell more than girls changing rooms in the school gym! The production of sperm from the testicles and eggs from the ovaries commences relatively late on during puberty. The first sperms appear in urine at the age of years, while ovulation does not generally occur until a couple of years after the first menstrual period. It should, however, be noted that a girl may be fertile following the first menstrual period! The onset of fertility cannot be determined based on chronological age, but rather by age at the onset of menstruation. Fact box: At birth, the testicles contain the early stages of sperms; however, mature sperms do not appear until a couple of years after the onset of puberty, when the testicles have grown to approximately 6-8 ml in volume. In adult males the testes produce approximately 2 million sperm per day. In girls, the maximum number of oocytes is reached at birth; thereafter there is a steady decline in numbers. At puberty, the oocytes mature and become fertile, one for each menstrual period. Sex hormones in adults After the onset of puberty, which does not conclude until the age of years in most girls and boys, the physical differences between boys and girls become even 5

6 more pronounced. The high levels of testosterone produce increased muscle mass in adolescent males, and increased growth of body hair (including facial hair!) and a deeper, more manly voice. In addition to menstruation, production of oestrogen by the girl s/woman s ovaries (in combination with progesterone produced by the corpus luteum) results in feminine fat distribution and continued growth of the breasts. Some increase in production of male hormones also takes place in girls, which explains why an adult woman has a somewhat deeper voice than a teenage girl. Where puberty is delayed as a result of family constitution or illness, the normal, rapid adolescent growth spurt (pubertal growth spurt) is also delayed. In the case of complete and permanent lack of sex hormones, the skeleton does not fully mature in adolescence, but growth instead continues at a much slower rate, up to an appreciable end height. Many years ago, boys were sometimes castrated prior to puberty in order to retain their soprano singing voice. Such male castrati were tall, with noticeably long arms and legs. They also had a lack of secondary hair growth and slight musculature compared to other men. Women and men perform differently in sports, and compete in different categories, but on what basis are they sorted into the correct category? Nearly all sports separate the competitors into two categories: Women and men (equestrian sports are exceptions). This is because with the same degree of training, the typical man almost always outperforms the typical woman. This is clearly illustrated by the fact that in respect of physical sports, the world records for men are generally around 10% better than for women. Consequently, it is seen as self-evident that men compete only against men, and women against women. This does not appear to be caused by XX and XY genes. There have been a number of unsuccessful attempts in the field of sports at objectively defining who can compete within the female category. At one time, the focus was one of "gender verification, i.e. that women would have to prove that they were women. When gene technology was refined, it was believed that by confirming the presence of two XX-chromosomes and the absence of Y-chromosomes, one could make a clear distinction between men and women, but it soon transpired that rarely, XY-individuals could in developmental terms be completely female (see above), and therefore should not be prevented from competing against other women. The issue of female gender caused a number of tragedies for those women who had grown up as - and perceived themselves to be - female. 6

7 Testosterone in the blood is the primary reason why men perform better in sport. The primary factor underlying man's superiority in performance sports is not their chromosomes, but their much higher levels of blood testosterone. (A healthy man has approximately 20 times higher levels of testosterone than a healthy woman). Testosterone stimulates muscle growth and muscle strength, and the increased aggressiveness that accompanies male sex hormones may also be a factor in competitive sports. The significance of androgenic hormones in relation to performance sports has long been understood in athletics. Consequently, punishments are harsh for those athletes who take illegal anabolic steroids, even in very small quantities. This applies to both men and women. Fact box: When we talk about anabolic steroids in the context of doping, this usually refers to synthetic steroids which have both an anabolic (tissue building) and an androgenic (stimulates male sexual characteristics) effect. Testosterone and most socalled anabolic steroids have both an anabolic and androgenic effect. Women with high levels of male sex hormones androgenism) The normal physical sexual development of both boys and girls is described above (see Fig 1). Each stage in the development has potential to malfunction during embryonic development, and during puberty. Excess male sex hormones For example; if the critical gene for the androgen receptors is severely damaged, then the foetus develops physically into a girl, despite the fact that she has male chromosomes, testicles and testosterone because she is insensitive to the male hormones (the syndrome of Androgen Insensitivity). Complete androgen insensitivity is not normally diagnosed prior to puberty, at which time girls seek medical help having failed to start menstrual periods and with almost no pubic hair growth. Such individuals, both during and after puberty, have extremely high production of testosterone from their testicles, but in terms of outward appearance and from a sporting perspective are completely female. Another factor that inhibits masculine development of a foetus is lack of the enzyme (5 -reductase), which converts testosterone to dihydrotestosterone (DHT). During the embryonic stage, DHT is important for development of the male genitalia. If the hormone is absent, the newborn child may be thought to be a girl, be given a girl's name and may grow up as a girl. However, an isoenzyme becomes functional during puberty which allows the conversion of testosterone to DHT and the body becomes more and more like a man s in terms of musclemass, since women with this development are normally sensitive to the high concentrations of testosterone pro- 7

8 duced by their testicles. 5 -reductase deficiency can cause problems within female elite sports. Some women with this deficiency experience remarkable improvements in their sporting performance during puberty, in parallel with the increasing levels of testosterone in the blood. In most cases such women are diagnosed and treated, but if they live in areas with poor standards of health care then they may fail to be diagnosed, and consequently may attend a world championship with a body that looks like a man s. In some cases this has caused their competitors, the public and journalists, to ask questions about their "true sex"; questions, which are of course deeply offensive to the woman concerned. How does one determine, within a sporting context, who can compete as a woman? The fundamental failure of sport historically in terms of management of cases where female competitors have been identified as male, stems from a failure to understand that the issue of sexual identity is one that can only be determined by the individual concerned. The person who sees herself as a woman is a woman, irrespective of what the biological markers show. There is no laboratory test that can determine an individual s sexual identity this can only be decided by the man or woman concerned. However, one can understand that for as long as athletes are determined to be either male or female competitors, a number of women are going to feel it is unfair that they have to compete against individuals who are physiologically capable of performing as a man. Consequently, since May 2011 the international Association of Athletic Federations (IAAF) has introduced restrictions in respect of maximum testosterone levels a woman may have during competition. Hence, all discussion of gender verification has been scrapped, and gender is never questioned. The issue instead is one of "hyperandrogenism", which in practice relates to women with high levels of blood testosterone and normal sensitivity for this. If the testosterone levels are as high as those of a healthy man, then the woman must be given medication in order to bring the levels below the normal male reference range. These regulations were also applicable during the 2012 Olympic Games in London. REFERENCES 1. The National Board of Health and Welfare's database of unusual diagnoses: yndromet 2. Wikipedia: IOC Regulations on Females with Hyperandrogenism: 8

9 mmission/ ioc-regulations-on-female-hyperandrogenismeng.pdf 4. IAAF Regulations Governing Eligibility of Females with Hyperandrogenism to Compete in Women s Competitions: _httppostedfile_HARegulations%28Final%29- Appendices-AMG _24299.pdf 9