8th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

Sexual hormones

P. Bischof, D. Islami
Department of  Obstetrics and Gynecology
Geneva University Hospital

1. INTRODUCTION

Sexual hormones are of two types: proteins and steroids. The steroids have a molecular weight of about 300 daltons, presenting thus a small size. Because of their size and lipo-solubility (soluble in fat), they can easily diffuse through target cells, having consequently intra-cellular receptors. While the protein hormones weigh more than 5.000 daltons and therefore cannot penetrate the cells, they need membrane receptors. The steroids can circulate in the blood stream, only if bound to non-specific proteins like albumin, or to specific proteins like SHBG (sex hormone binding globulin). On the other hand, the protein hormones are hydro-soluble and circulate freely in the blood.

2. THE PROTEIN HORMONES

2.1 The gonadotropins

These hormones are produced by different tissues (pituitary and placenta) and their main function is gonadic regulation (ovaries and testicles). The gonadotropins include: FSH ( folliculo-stimulating hormone), LH (luteinizing hormone) and hCG (human chorionic gonadotropin).

2.1.1 Folliculo-stimulating hormone (FSH)

FSH is a glycoprotein produced by the pituitary gland and has a molecular weight of about 30.000 daltons. Morphologically, it is a heterodimer composed by two different sub-units: a and b . The a sub-unit (89 aminoacids) is common to all gonadotropins and also to TSH (thyrotrophic hormone). The b sub-unit (118 aminoacids) is specific for FSH. The main function of FSH is to promote and sustain the ovarian follicular growth in women and the spermatogenesis in men. FSH stimulates also the synthesis of its own receptor on the granulosa and Sertoli cells and the LH receptor on granulosa cells. It stimulates the aromatase activity inside the granulosa cells (the enzyme converting the androgens into oestrogens). Thus, FSH is responsible for " the choice of the dominant follicle". FSH synthesis and secretion by the hypophysis is controlled by different regulators, like: GnRH (gonadotropin releasing hormone of hypothalamic origin), ovarian oestrogens, activine and inhibine (both of gonadic origin).

2.1.2 Luteinizing hormone (LH)

LH is a glycoprotein with a molecular weight of approximately 30.000 daltons, and produced by the hypophysis. Like FSH, LH is also present as a heterodimer with two different sub-units: a and b . The principal functions of LH are: 1. promoting the androgen synthesis in the thecal cells of the ovaries and in the interstitial cells of the testicles, 2. inducing ovulation (by stimulating the cascade of proteolytic enzymes leading to the rupture of basement membrane of the follicle) and 3. maintaining the corpus luteum during the menstrual cycle. LH synthesis and secretion from the hypophysis is controlled by different regulators, like GnRH (gonadotropin releasing hormone of hypothalamic origin) and ovarian oestrogens and progesterone.

2.1.3 Human chorionic gonadotropin (hCG)

hCG is a glycoprotein with a molecular weight of about 43.000 daltons, produced by the syncytiotrophoblast. It is a heterodimer composed by two different sub-units: a and b . The specific b sub-unit contains 145 aminoacids and can be distinguished from the b sub-unit of LH only by 30 aminoacids in the C terminal part of the molecule. The whole molecule of hCG is also called holo-hCG, in order to be distinguished from total hCG, currently measured in the labs, (holo-hCG + free b sub-unit). The free b sub-unit circulates also in the blood. A particular form of hCG, called "nicked" hCG, is a holo-hCG or a free b sub-unit, where the bond between the 46th and the 47th aminoacid is broken. This gives rise to a particular tri-dimensional form of the molecule, making it often difficult to be recognised by the antibodies used for its measurement. The immunological recognition of "nicked" forms is specially important when hCG is measured to determine the risk of a mother to carry a trisomy 21 baby ( known as the "What if, double test or triple test"), as in this chromosomal pathology, the "nicked" forms increase significantly. The function of hCG is essential to maintain the corpus luteum of pregnancy and its progesterone secretion. But it has also an anti-gonadotrophic effect, as it inhibits the secretion of LH and FSH. hCG is said to be a "steroidogenic" hormone, not only because it favours the secretion of progesterone by the corpus luteum , but also because it stimulates the steroid secretion from foetal gonads. The regulation of hCG synthesis and secretion is provided by a trophoblastic GnRH.

2.2 Prolactin (Prl)

Human prolactin is a non-glycosylated protein, which contains a simple polypeptide chain of 198 aminoacids. It is structurally similar to hPL (human placental lactogen) and to growth hormone (GH). In the circulation, prolactin can appear in its monomeric (little prolactin) or polymeric form (big or big-big prolactin), as well. The quantitative relationship between these different forms varies according to physiologic and pathologic conditions and according to the antibody used for their measurement. Prolactin is essentially of pituitary origin, but the stromal cells of the endometrium produce prolactin during the secretory phase, as well. This hormone is considered as a marker of decidualisation. The principal biological function of prolactin in women is to control breast development and lactation. The role of prolactin in men and of endometrial prolactin in women is not yet known. If progesterone is the main regulator of endometrial prolactin, the pituitary prolactin is essentially controlled by dopamine (called also PIF or prolactin inhibiting factor). However, TRH (thyroid releasing hormone) and VIP (vasoactive intestinal peptide) are capable of stimulating the release of pituitary prolactin.

3. THE STEROID HORMONES

3.1 Oestrogens

Oestrogens are of three types: oestrone (E1), oestradiol (E2) and oestriol (E3). At equal concentrations, E2 has a stronger biological effect than E1 which is more powerful than E3. E2 can be reversibly converted to E1 and E1-sulphate. This sulphate is quantitatively the most important metabolite in the circulation. The enzymatic conversion of oestrogens occurs in the liver. Oestrogens are excreted in the urine as glucuronides or sulphates.

3.1.1 Oestradiol (E2)

In women of reproductive age, E2 is essentially produced by the enzymatic conversion of androgens (androstenedione and testosterone). The androgens are produced by the thecal cells under the influence of LH and their conversion in E2 occurs in the granulosa cells of the follicle, through the enzyme aromatase. Aromatase activity depends on FSH levels. Thus, a harmonious secretion of E2 is dependent on the two pituitary gonadotropins. In the post-menopausal women, the low level of E2 is provided by peripheral (liver, fat and muscular tissues) conversion (aromatisation) of androgens secreted by the adrenal glands. In men, 20% of circulating E2 is provided by a Sertoli cell production and 80% comes from the peripheral conversion of androgens. The principal functions of E2 in women is the mitotic effect on the uterine mucosa and on the breast, the feed-back (positive and negative) on pituitary gonadotropins and its role in bone mineralisation.

3.1.2 Oestrone (E1)

In women of reproductive age, E1 is mainly produced from the enzymatic conversion of androstenedione, which is secreted under the influence of LH by the thecal cells. The aromatase activity depends on FSH. In the menopausal women and in men, E1 and its sulphate represent the main circulating oestrogens. The biological function of E1 is still speculative, but it could be related to the regulatory effect that the conversion of E1 into E2 has on the degree of oestrogenisation.

3.1.3 Oestriol (E3)

In women of reproductive age, the very low concentrations of E3 are produced by hepatic hydroxylation of E1 and E2. During pregnancy, E3 is produced in large quantities from the foeto-placental unit. As 17-hydroxylase is lacking in the placenta and 3-b -hydroxy-dehydrogenase is absent in the foetus, the E3 production is dependent on a foeto-placental collaboration. The mechanism is as follows, placental pregnenolone (the precursor of progesterone) is reduced to dehydroepiandrosterone sulphate (DHEAS) in the foetal adrenal glands. DHEAS returns to the placenta, where it is transformed into androstenedione and then into E3. The E3 concentrations strongly increase during pregnancy, reflecting thus the foeto-placental co-operation. For this reason the level of E3 has been used for a long time to assess high-risk pregnancies. The biological role of E3 remains still unknown.

3.2 Progesterone (P4)

In non-pregnant women of reproductive age, P4 is essentially of ovarian origin, the participation of the adrenal cortex is negligible. In the middle of the menstrual cycle, it is the LH peak which induces biochemical and phenotypical changes of granulosa cells, called also "the process of luteinisation". This process makes the granulosa cells capable to produce progesterone. Thus, progesterone, which becomes detectable from midcycle onwards, is essentially produced by the corpus luteum. In the beginning of pregnancy (< 12 weeks), P4 is also produced by the corpus luteum; after 12 - 14 weeks of pregnancy the synthesis and production of P4 are exclusively of placental origin The biological role of P4 is to transform the uterine mucosa, already stimulated by E2, in a secretory mucosa, which can receive a fertilised ovum. On the other hand, progesterone inhibits uterine contractions. Progesterone synthesis in the corpus luteum is stimulated by LH and hCG. The regulation of progesterone production in the placenta is not yet known, but it is thought to be partly dependent on hCG.

3.3 Testosterone (T)

In women of reproductive age, T is produced by the thecal cells which surround the follicle. This androgen (T) serves as a substrate for the synthesis of E2, but it is also detected in circulation, even in very low concentrations. In men testosterone is produced by Leydig cells, but the contribution of adrenal androgens cannot be neglected, especially in certain pathologies of the new born. The biological role of T in women is to favour follicular atresia (a follicle which has a diminished capacity of aromatisation cannot aromatise all androgens becomes atretic). In men, T provides the appearance of secondary sex characteristics (voice, pilosity) and controls gonadotropins secretion.