Mammalian ovaries consist of follicles as basic functional units. The total number of ovarian follicles is determined early in life, and the depletion of this pool leads to reproductive senescence. Each follicle develops to either ovulate or, more likely, to undergo degeneration. The dynamics of ovarian follicle development have interested endocrinologists and developmental biologists for many years. With the advent of assisted reproductive techniques in humans, the possibility of regulating follicle development in vivo and in vitro has gained clinical relevance. In this review, we focus upon key branching points during the development of ovarian follicles as well as factors involved in determining the eventual destiny of individual follicles. We discuss inconsistencies in the literature regarding the definitions of follicle recruitment and selection and propose to name the two major steps of follicle development as initial and cyclic recruitment, respectively. Because some of these disparities have arisen due to differences in the animal systems studied, we also compare the development of the ovarian follicles of both humans and rats. We also review the status of knowledge of several puzzling clinical issues that may provide important clues toward unlocking the mechanisms of follicle development.

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Initial and cyclic recruitment of ovarian follicles.

This report describes the development of a specific and sensitive assay for inhibin B and its application to the measurement of inhibin B concentrations in plasma during the human menstrual cycle. A monoclonal antibody raised against a synthetic peptide from the betaB-subunit was combined with an antibody to an inhibin alpha-subunit sequence in a double antibody enzyme-linked immunosorbent assay format. The validated assay had a limit of detection of 10 pg/mL and 0.5% cross-reactivity with inhibin A. Using this immunoassay, we found that the plasma concentration of inhibin B rose rapidly in the early follicular phase to a peak of 85.2 +/- 9.6 pg/mL on the day after the intercycle FSH rise, then fell progressively during the remainder of the follicular phase. Two days after the midcycle LH peak, there was a short lived peak in the inhibin B concentration (133.6 +/- 31.2 pg/mL), which then fell to a low concentration (<20 pg/mL) for the remainder of the luteal phase. In contrast, the inhibin A concentration...

Measurement of dimeric inhibin B throughout the human menstrual cycle.

An extensive literature dealing with studies on the pathophysiology of the polycystic ovary syndrome (PCO) has accumulated over the years. The great clinical and biochemical variability of PCO, as indicated in several excellent reviews over a decade ago (Goldzieher & Axelrod, 1963; Mahesh & Greenblatt, 1964; Jeffcoate, 1963; Shearman & Cox, 1966), continues as a major problem in defining this syndrome. Further, the pathogenesis of this reversible disorder remains elusive. However, recent advances in our understanding of ovarian physiology, the pathways for androgen-oestrogen secretion and metabolism, and the integrated function of the hypothalamic-hypophyseal-ovarian axis permit a rational description of the pathophysiology of the PCO syndrome. Thus, current evidence regarding the basis for the dysfunction of ovarian steroidogenesis and follicular maturation, and the aberration of gonadotropin secretion as related to the inappropriate steroid feedback system will be reviewed. The long debated issue of the possible role of adrenal androgen in the genesis and persistence of PCO syndrome will also be considered.

Review article: the polycystic ovary syndrome

Studies of menstrual cycle length in large populations demonstrated that there is a striking increase in the variability of intermenstrual intervals just before menopause. The changes in serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and progesterone (P) during menstrual cycles in a group of perimenopausal women were compared with the findings in young normal women. In 8 women, 46-56 years old with regular cycles, cycle length was shorter and the mean E2 concentration was lower than in younger women. There was a striking increase in FSH concentration throughout the cycle while LH remained in the normal range. In 2 women, 14 cycles of variable length were studied during 2 years of the menopausal transition. In some instances, hormonal changes associated with follicular maturation and corpus luteum function occurred in the presence of high, menopausal levels of LH and FSH with a diminished secretion of E2 and P. In others vaginal bleeding occurred during a fall in serum E2 with no associated rise in P. Cycles of variable length during the menopausal transition may be due either to irregular maturation of residual follicles with diminished responsiveness to gonadotropin stimulation, or to anovulatory vaginal bleeding that may follow estrogen withdrawal without evidence of corpus luteum function. The observation of elevated FSH concentrations and normal LH levels in perimenopausal women emphasizes the complexity of the hypothalamic-pituitary-ovarian regulatory system and suggests that LH and FSH are modulated independently at the level of the pituitary.

The Menopausal Transition: Analysis of LH, FSH, Estradiol, and Progesterone Concentrations During Menstrual Cycles of Older Women

The 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase (3beta-HSD) isoenzymes are responsible for the oxidation and isomerization of Delta(5)-3beta-hydroxysteroid precursors into Delta(4)-ketosteroids, thus catalyzing an essential step in the formation of all classes of active steroid hormones. In humans, expression of the type I isoenzyme accounts for the 3beta-HSD activity found in placenta and peripheral tissues, whereas the type II 3beta-HSD isoenzyme is predominantly expressed in the adrenal gland, ovary, and testis, and its deficiency is responsible for a rare form of congenital adrenal hyperplasia. Phylogeny analyses of the 3beta-HSD gene family strongly suggest that the need for different 3beta-HSD genes occurred very late in mammals, with subsequent evolution in a similar manner in other lineages. Therefore, to a large extent, the 3beta-HSD gene family should have evolved to facilitate differential patterns of tissue- and cell-specific expression and regulation involving multiple signal transduction pathways, which are activated by several growth factors, steroids, and cytokines. Recent studies indicate that HSD3B2 gene regulation involves the orphan nuclear receptors steroidogenic factor-1 and dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1 (DAX-1). Other findings suggest a potential regulatory role for STAT5 and STAT6 in transcriptional activation of HSD3B2 promoter. It was shown that epidermal growth factor (EGF) requires intact STAT5; on the other hand IL-4 induces HSD3B1 gene expression, along with IL-13, through STAT 6 activation. However, evidence suggests that multiple signal transduction pathways are involved in IL-4 mediated HSD3B1 gene expression. Indeed, a better understanding of the transcriptional factors responsible for the fine control of 3beta-HSD gene expression may provide insight into mechanisms involved in the functional cooperation between STATs and nuclear receptors as well as their potential interaction with other signaling transduction pathways such as GATA proteins. Finally, the elucidation of the molecular basis of 3beta-HSD deficiency has highlighted the fact that mutations in the HSD3B2 gene can result in a wide spectrum of molecular repercussions, which are associated with the different phenotypic manifestations of classical 3beta-HSD deficiency and also provide valuable information concerning the structure-function relationships of the 3beta-HSD superfamily. Furthermore, several recent studies using type I and type II purified enzymes have elegantly further characterized structure-function relationships responsible for kinetic differences and coenzyme specificity.

Molecular Biology of the 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4 Isomerase Gene Family

Nineteen regularly menstruating women were given either 0.1 mg of ethinyl estradiol alone or in combination with 200 mg of clomiphene citrate for 8 consecutive days starting with the onset of menses. Ethinyl estradiol decreased plasma FSH concentrations and abolished the normal progressive follicular rise of LH. Five to 9 days after discontinuing ethinyl estradiol, 7 of 10 subjects had withdrawal bleeding. When clomiphene was given with ethinyl estradiol, gonadotropin levels were normal throughout the cycle and there was no withdrawal bleeding. Plasma 17-hydroxyprogesterone levels in the latter treatment group were higher than those in the ethinyl estradiol group, although in neither group were 17-hydroxyprogesterone or progesterone levels consistent with normal corpus luteum function. Short luteal phases were encountered in both groups. When subjects, irrespective of treatment, were categorized according to duration of luteal phase, then those women with luteal phases of 10 days or less had lowe...

New Evidence for an Anti-estrogenic Action of Clomiphene Citrate in Women

This is the first report of a child with the 3β-hydroxysteroid dehydrogenase (3β-HSD) defect to have reached a pubertal age. This 13-yr-old boy's puberty was manifested by the development of male secondary sexual characteristics and marked gynecomastia. Clinical support for the diagnosis consisted of his marked salt-wasting, hypospadias and family history of 2 infants who died with congenital adrenal hyperplasia and ambiguous external genitalia. Laboratory support for the diagnosis consisted of greatly elevated plasma pregnenolone,6 17-OH-pregnenolone and DHEA, as well as high urinary pregnenetriol and DHEA. The paradoxical presence of progesterone in blood and of pregnanetriol, androsterone and etiocholanolone in the urine of this and other patients probably results from peripheral conversion of pregnene compounds by liver 3β-HSD enzymes to pregnane compounds. In this patient there was a rise in plasma testosterone following human chorionic gonadotropin administration, suggesting that the pubert...

Pubertal Boy with the 3β-Hydroxy steroid Dehydrogenase Defect

The peripheral venous plasma concentrations of pregnenolone (Δ5-P), 17-hydroxypregnenolone (Δ5-17-OHP), progesterone (P), 17-hydroxyprogesterone (17-OHP), and cortisol were measured in 5 normal men during a 3-hour infusion of ACTH The concentrations of Δ5-P, Δ5-17-OHP reached levels 4 to 6 times those of control samples, whereas progesterone, 17-OHP, and cortisol concentrations had only doubled We propose that ACTH causes preferential stimulation of the Δ5 pathway for cortisol biosynthesis

Early adrenal response to ACTH; Plasma concentrations of pregnenolone, 17-hydroxypregnenolone, progesterone, and 17-hydroxyprogesterone.

We have investigated the hypothesis that orally administered exogenous estrogen might exert differing effects upon circulating levels of plasma FSH and LH depending upon the time of administration during the menstrual cycle. Ethinyl estradiol (EE), 100 μg/day, was administered to 7 normal volunteers from days 9–18, counting the day of onset of menses as day 0. Plasma FSH and LH concentrations were compared to those from 7 untreated controls. FSH showed a transitory elevation, marked decline, and prominent rebound following cessation of EE. LH showed a sustained elevation during EE therapy, with a maximum elevation near midcycle. Maximal levels of FSH and LH, which occurred concomitantly in controls, were dissociated in 6 of 7 women receiving EE. These results were contrasted to those observed when the same dose of EE was administered from cycle days 0–7 (1) when suppression of both FSH and LH was noted without the occurrence of peaks during therapy. These results provide evidence that the effect of orally...

Jose A. Bermudez

Papers

New Evidence for an Anti-estrogenic Action of Clomiphene Citrate in Women

Pubertal Boy with the 3β-Hydroxy steroid Dehydrogenase Defect

Early adrenal response to ACTH; Plasma concentrations of pregnenolone, 17-hydroxypregnenolone, progesterone, and 17-hydroxyprogesterone.

A differential effect of ethinyl estradiol upon plasma FSH and LH relating to time of administration in the menstrual cycle.

Saturation assays for plasma progesterone and 17-hydroxyprogesterone.