Differential Control of Gonadotropin Secretion in the Human: Endocrine Role of Inhibin1

Frances J. Hayes, Janet E. Hall, Paul A. Boepple and William F. Crowley, Jr.

Reproductive Endocrine Unit and National Center for Infertility Research, Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Frances J. Hayes, M.B., M.R.C.P.I., Reproductive Endocrine Unit and the National Center for Infertility Research, Massachusetts General Hospital, BHX 5, Fruit Street, Boston, Massachusetts 02114.


    Introduction
 Top
 Introduction
 The inhibin hypothesis
 Difficulties in charting inhibin...
 Inhibin physiology in the...
 References
 
THE regulation of gonadotropin secretion in the human involves a complex interplay between stimulation by GnRH from the hypothalamus, inhibitory feedback by sex steroids and inhibin(s) from the gonads, and autocrine/paracrine modulation by activin and follistatin within the pituitary. It was initially believed that two different hypothalamic factors regulated the secretion of LH and FSH. However, it is now generally accepted that GnRH is the stimulating factor for both hormones and that any divergence in their secretion can be explained by differential sensitivities of LH and FSH to variations in the dose or frequency of pulsatile GnRH secretion, the gonadal hormonal milieu including sex steroid and nonsteroidal factors, and/or alterations in the pituitary tone of activin and/or follistatin. The nonsteroidal regulation of FSH in the human is mediated by the opposing effects of inhibin and activin, with inhibin selectively suppressing, and activin stimulating, FSH release (1). Follistatin, although structurally unrelated to inhibin, also suppresses FSH secretion by binding to activin, thereby modulating its bioavailability. It is the purpose of this review to provide perspective on the endocrine role of gonadal inhibin A and inhibin B in the differential control of LH and FSH secretion in the human, although data from the nonhuman primate will be included to address issues not yet studied in the human.


    The inhibin hypothesis
 Top
 Introduction
 The inhibin hypothesis
 Difficulties in charting inhibin...
 Inhibin physiology in the...
 References
 
The original basis for the "inhibin hypothesis" was the demonstration 65 yr ago that an aqueous testicular extract could suppress the formation of castration cells in the anterior pituitary, suggesting a physiological role for a nonsteroidal gonadal secretory product and thus dual endocrine activity of the testis (2). Subsequently, more than 50 yr elapsed before the isolation and characterization of inhibin in the mid-1980s (1, 3). Many of the difficulties encountered in the effort to isolate inhibin arose as a direct result of the complex protein chemistry of the inhibin members of the transforming growth factor-ß superfamily of proteins.

Inhibin is a glycoprotein hormone secreted by the Sertoli cells of the testis and the granulosa and theca cells of the ovary. It is composed of an {alpha}-subunit disulfide-linked to one of two ß-subunits, the ßA-subunit to form inhibin A or the ßB-subunit to form inhibin B (1). A variety of molecular forms are present in the circulation, including mature (32-kDa) and partially processed {alpha}ß-dimers, as well as free {alpha}-subunit forms. Although the free {alpha}-subunits lack biological activity, the larger molecular mass dimers as well as inhibin A and inhibin B have been shown to have the ability to suppress FSH secretion (4).


    Difficulties in charting inhibin physiology
 Top
 Introduction
 The inhibin hypothesis
 Difficulties in charting inhibin...
 Inhibin physiology in the...
 References
 
Despite the triumphs of protein chemistry and molecular biology that led to the characterization of the inhibins, numerous methodological difficulties have plagued efforts to explore their physiology. Given the high degree of structural homology between different members of the inhibin family, the development of specific, high affinity antibodies has proven difficult. The pioneering heterologous polyclonal RIA generated to bovine inhibin (5) used in the initial studies of inhibin in the human suffered from problems with specificity. As the antisera exhibit complete epitopic specificity for amino acids 93–108 in the C-terminus of the {alpha}-subunit (6), this RIA, which is commonly known as the Monash assay, is incapable of distinguishing {alpha}-subunit precursor proteins from biologically active dimeric inhibins (7, 8). Although this (9) and other (10) assays of total inhibin may have an important role as markers of granulosa cell or mucinous epithelial tumors of the ovary, they fail to reflect the dynamic secretion of the dimeric inhibins. This limitation is particularly relevant given that {alpha}-subunit proteins are present in abundance in the circulation, arise at least in part from extragonadal sources (11), and may be regulated in a different direction from that of the dimeric inhibins (12). In the last 3 yr, important technological advances have been made with the development of sensitive, highly specific two-site enzyme-linked immunosorbent assays (ELISAs) incorporating a specific capture antibody to either the ßA- or ßB-subunit as well as a mouse monoclonal detection antibody directed against the N-terminal portion of the 20-kDa inhibin {alpha}-subunit (13, 14). Although the first of these ELISAs was initially thought to measure all dimeric inhibin (13), it became apparent with the development of a suitable inhibin B standard that this assay was, in fact, specific for inhibin A, with less than 0.15% cross-reaction with recombinant inhibin B (14).

An additional problem encountered in the inhibin field has been the lack of inhibin preparations in sufficient quantity and purity to administer to humans. To date, therefore, most of the evidence for the participation of inhibins in differential gonadotropin control in the human has been based upon correlative studies rather than experimental manipulations. Finally, there appears to be important species specificity in the relative role of inhibin in gonadotropin feedback; e.g. rats have a considerably lower FSH response to inhibin antibody administration than do nonhuman primates (15, 16). For all of these reasons, inferences about inhibin physiology in the human are limited and indirect.


    Inhibin physiology in the adult male
 Top
 Introduction
 The inhibin hypothesis
 Difficulties in charting inhibin...
 Inhibin physiology in the...
 References
 
Descriptive studies.

Sites of inhibin subunit gene expression: Data on the localization of inhibin subunits in the human male are derived from fetal and early postnatal, rather than adult, testes. Immunocytochemical studies employing purified monoclonal antibodies have demonstrated the presence of {alpha}- and ßB-inhibin subunits predominantly in the Sertoli cells and, to a lesser extent, in the Leydig cells of the testis (17). Consistent with the absence of circulating inhibin A in male serum, immunostaining against the ßA-subunit has been negative.

Inhibin levels in normal and infertile men: Testing one of the basic tenants of the inhibin hypothesis, namely that there should be an inverse relationship between serum inhibin and FSH levels, has proven difficult in intact models because gonadotropin stimulation of a functioning testis is known to increase inhibin secretion. Thus, the alterations in gonadal stimulation associated with normal puberty, endogenous gonadotropin suppression, and exogenous gonadotropin administration are all marked by parallel changes in inhibin and FSH (18). When the inhibin hypothesis was initially tested in various clinical models of primary and secondary hypogonadism, a reciprocal relationship between serum inhibin and FSH was not observed; indeed, inhibin levels were shown to be normal or even raised in men with severe spermatogenic failure (19). This raised doubts about the physiological relevance of inhibin in the male until it was recognized that the Monash RIA used in these studies had cross-reactivity of up to 288% with the biologically inactive {alpha}-subunit (7, 8).

Studies using an assay initially thought to measure total dimeric inhibin, but which was subsequently found to have only minimal cross-reactivity with recombinant inhibin B (14), showed that inhibin levels were virtually undetectable in normal and GnRH-deficient men (20). With the development of assays specific for inhibin A, Illingworth et al. demonstrated that in both normal men and men with reproductive disorders, inhibin A concentrations were too low to be of physiological relevance as an endocrine signal (21). Subsequently, a two-site ELISA for inhibin B demonstrated an inverse relationship between inhibin B and FSH across a wide range of FSH concentrations in normal and infertile men (21, 22, 23), consistent with a potential role of inhibin B as an endocrine feedback regulator of FSH secretion in the male.

Experimental studies.

Inhibin administration and immunoneutralization in the subhuman primate: Studies in the monkey have demonstrated that treatment of gonadectomized males with recombinant inhibin A prevents the castrate rise in pituitary FSHß messenger ribonucleic acid (mRNA) levels and circulating FSH concentrations (24). Although these data initially suggested a critical role for inhibin in the regulation of FSH secretion, it is important to note that the serum levels of inhibin A achieved were found to be pharmacological rather than physiological when remeasured with the inhibin A ELISA (25). In addition, although there are presently no data to suggest that inhibin A and inhibin B differ in potency, it is inhibin B, rather than inhibin A, that appears to be the physiologically relevant inhibin in male monkeys and adult men (20, 21, 25). However, despite these reservations, immunoneutralization experiments support an endocrine role for inhibin in the male with the demonstration that a continuous infusion of an antiserum to the N-terminal portion of human {alpha}-inhibin subunit in male macaques results in a 2- to 3-fold increase in circulating FSH concentrations (16).

Inhibin B levels: A number of studies have explored the inhibin B response to a variety of hormonal manipulations in normal and infertile men (22, 23, 26). Our group has previously chronicled the serial changes in inhibin B during the experimental induction of sexual maturation with exogenous GnRH in men with isolated GnRH deficiency (22, 23). At baseline, inhibin B levels in GnRH-deficient men were significantly lower than those in normal controls, but showed a surprising degree of variation. Although more than one third of patients had levels at or below the working range of the assay, several had concentrations well within the normal adult range. Correlational analysis revealed that two interrelated factors showed a strong positive relationship with inhibin B: pretreatment testicular volume and a prior history of some degree of spontaneous puberty (Fig. 1Go). The higher inhibin B levels observed in patients with a history of puberty and, therefore, higher testicular volume, suggest that prior stimulation of the testis sufficient to induce seminiferous tubular maturation has an abiding impact on inhibin B secretion that is sustained after sexual maturation. This hypothesis of a developmental threshold for testicular inhibin B secretion is supported by the pattern of inhibin B secretion observed in boys with central precocious puberty (CPP). In this model, inhibin B concentrations are in the normal adult range at the time of active precocity, but during treatment with a GnRH analog at a dose sufficient to render gonadotropins undetectable, they fall to levels that remain easily detectable, similar to the concentrations found in GnRH-deficient men with a history of spontaneous puberty (27).



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Figure 1. Inhibin B vs. testicular volume at baseline in GnRH-deficient men with and without a history of prior puberty. The shaded area represents the mean ± 2 SD of 20 normal adult men. The assay sensitivity of 50 pg/mL is indicated by the dashed line. This was reproduced with permission from the authors (23).

 
In GnRH-deficient men, treatment with pulsatile GnRH to normalize testosterone, LH, and FSH resulted in a significant increase in mean inhibin B levels, with the greatest impact in subjects without prior history of puberty (Fig. 2Go). A significant inverse relationship existed between inhibin B and FSH during both acute (first 8 weeks; Fig. 3Go) and chronic (up to 1 yr) GnRH replacement. However, despite normal LH, FSH, and testosterone levels during GnRH therapy, inhibin B levels remained significantly lower than those in normal controls. Further studies are required to elucidate whether these lower inhibin levels reflect an intrinsic testicular defect, inadequate duration of GnRH therapy, or the presence of a developmental window during which gonadotropin stimulation of the testis is critical to subsequent testicular function in later life (28).



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Figure 2. Serial inhibin B determinations in GnRH-deficient men during long term GnRH replacement. Individual values are indicated by open and closed circles; group means are represented by the horizontal lines. The shaded area represents the mean ± 2 SD of 20 normal adult men. NEM refers to the point of neuroendocrine maturation, as defined by the consistent establishment of normal concentrations of LH, FSH, and testosterone. + 6 m and + 12 m refer to treatment with GnRH for 6 and 12 months, respectively. This was reproduced with permission from the authors (23).

 


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Figure 3. Serum FSH concentrations plotted against inhibin B levels after pulsatile GnRH replacement in 16 men with GnRH deficiency. Measurements are from pooled blood samples obtained after 8 weeks of GnRH treatment (50 ng/kg every 2 h). This was reproduced with permission from the authors (22).

 
Response to gonadotropin suppression and stimulation with recombinant FSH: The study of men with a spectrum of reproductive disorders (idiopathic hypogonadotropic hypogonadism, Klinefelter’s syndrome, oligo/azoospermia with elevated FSH levels, and postorchidectomy) has provided evidence that inhibin B secretion is limited to the testis. Inhibin B levels were undetectable in agonadal men and were significantly lower than normal in men with other testicular disorders (26). This study also illustrates the gonadotropin dependence of gonadal inhibin B secretion, with levels decreasing after suppression of endogenous gonadotropins by levonorgestrel and testosterone administration and increasing after stimulation by recombinant FSH.

As inhibin B secretion is dramatically lowered in primary testicular disorders, a recent study explored whether differences in the degree of suppression of spermatogenesis after exogenous testosterone administration could be assessed by changes in circulating concentrations of inhibin B (29). During testosterone treatment, FSH levels fell rapidly, followed by a parallel decline in inhibin B and sperm concentrations. However, there was no difference in the inhibin B levels, either before treatment or during therapy, between men rendered azoospermic and those in whom sperm continued to be present in the ejaculate. Thus, measurement of plasma inhibin B was of no value in predicting the spermatogenic response to sex steroid administration for contraceptive purposes. The observation that inhibin B levels only fell to 30% of baseline despite undetectable gonadotropin levels is consistent with our data in men with GnRH deficiency and boys treated for precocious puberty (23, 27). Similar evidence is provided by studies in the monkey, in which inhibin B concentrations in juveniles were approximately 40% higher than those in infants, despite the fact that the juvenile period is characterized by marked hypogonadotropism (25). These data provide consistent support for a gonadotropin-independent component to inhibin B secretion in the male that is abolished only in the presence of primary testicular disease, suggesting that inhibin secretion from Sertoli cells may be regulated by interaction with germ cells (30).

Response to induction of Sertoli cell damage: In a prospective study of men with hematological malignancies treated with chemotherapy, the dynamic relationship between inhibin B and FSH was examined during progression from normal to severely impaired seminiferous tubular function (12). Within 4 months of commencing chemotherapy, inhibin B levels had fallen to 20% of the baseline values accompanied by a reciprocal 5-fold rise in FSH, yielding an inverse correlation between the two hormones. In contrast to the levels of dimeric inhibin B, total immunoreactive inhibin levels measured by the Monash RIA remained unchanged, whereas pro-{alpha}C-containing inhibins increased significantly, correlating directly with the rising FSH level. This novel observation that a testicular insult is associated with an increase in pro-{alpha}C-containing inhibin forms is consistent with the in vitro demonstration that FSH stimulates free {alpha}-subunit secretion in Sertoli cell cultures (31). The reciprocal changes seen in inhibin B and free {alpha}-subunit secretion in response to Sertoli cell damage provide for the first time a definitive explanation for the normal total immunoreactive inhibin levels in men with spermatogenic failure reported in previous studies using the Monash RIA (19).

Summary of inhibin physiology in the male: These studies indicate that inhibin B is the physiologically important form of inhibin in the human male. Although inhibin B is stimulated by FSH, there is also evidence for a gonadotropin-independent component to its regulation in men. Inhibin B appears to play a significant role in the negative feedback loop regulating FSH secretion and may provide a useful marker of Sertoli cell function.

Inhibin physiology in the female

Descriptive studies. The role of inhibin in female reproductive physiology has been explored using a number of approaches, including the determination of specific inhibin subunit mRNA expression in the ovary as well as the concentration of circulating immunoreactive inhibins across the menstrual cycle.

Sites of inhibin subunit gene expression: In a variety of species, including the human, a changing pattern of inhibin subunit mRNA expression has been demonstrated in ovarian granulosa, theca, and lutein cells across the reproductive cycle (32). Expression of the ßA-subunit is highest in the corpus luteum and the dominant follicle; that of ßB is greatest in the granulosa cells of antral follicles during the luteal-follicular transition, whereas expression of the {alpha}-subunit appears relatively constant throughout follicular development after the antral stage.

Immunoreactive inhibin levels across the menstrual cycle: The Monash polyclonal RIA initially showed inhibin to be detectable throughout the normal menstrual cycle. Inhibin levels were low in the early to midfollicular phase, rose in the late follicular phase to a peak on the day of the midcycle LH surge, then fell briefly after ovulation before reaching a maximum in the midluteal phase (33). When similar studies were conducted with the two-site ELISA specific for dimeric inhibin A (13, 20, 34), the overall pattern of inhibin secretion across the menstrual cycle was similar to that seen with the Monash assay, except that the magnitude of the changes observed was greater. The peak in inhibin A in the luteal phase and its fall with luteolysis are consistent with its being a secretory product of the corpus luteum, as would be expected from the expression of the ßA-subunit in the corpus luteum (32). The inverse correlation between inhibin A and FSH levels in the luteal phase suggests that release from the negative feedback effect of inhibin may play a role in the rise in FSH and, thereby, the initiation of follicular development during the luteal-follicular transition. However, it has been suggested that the control of FSH during this critical phase may be entirely due to estradiol (35).

With the lack of change in inhibin A levels in the midfollicular phase of the cycle, it initially appeared unlikely that inhibin was playing any endocrine role in the fall in FSH observed at this time. However, using the inhibin B-specific ELISA, patterns of differential secretion of inhibin B and A secretion were subsequently documented across the menstrual cycle (14, 34) (Fig. 4Go). Plasma concentrations of inhibin B are maximal in the early and midfollicular phases, falling in the late follicular phase before ovulation and then, after a brief postovulatory rise, reaching a nadir in the midluteal phase. During the luteal-follicular transition, inhibin B levels rise rapidly, reaching a maximum 4 days after the peak in FSH. The timing of the early follicular phase rise in plasma inhibin B and the positive correlation with FSH (34) suggest that inhibin B is secreted by small developing follicles in response to FSH stimulation. The source of the peak in inhibin B on the day after ovulation is thought to represent release from the ruptured follicle, rather than secretion from the corpus luteum, as the latter does not express mRNA for the ßB-subunit. The inability of the Monash assay to detect the follicular phase rise in inhibin B secretion was subsequently explained by the demonstration that this assay detects dimeric inhibin A to a far greater degree than inhibin B (36). It has been suggested that inhibin B may have an endocrine role in the fall in FSH that occurs in the late follicular phase (14). However, studies to date have not distinguished a potential negative feedback effect of inhibin B on FSH secretion from that of estradiol at this cycle stage.



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Figure 4. Mean ± SEM daily inhibin A, inhibin B, FSH, estradiol, and progesterone levels in the luteal-follicular transition of normal cycling women. Data are centered to the day of menses in cycle 2. This was reproduced with permission from the authors (34).

 
Comparison of inhibin levels in older vs. younger cycling women: One of the areas of increasing interest in female reproductive endocrinology is the hormonal milieu during the early phase of reproductive aging, a time when there is a selective rise in FSH levels. Given that no significant changes have been observed in ovarian steroid secretion at this time, it has been postulated that early decreases in ovarian inhibin secretion might account for the monotropic FSH rise seen in older, ovulatory women. Initial studies measuring total immunoreactive inhibin demonstrated that inhibin levels were decreased in perimenopausal women and were undetectable in postmenopausal women (37). In a correlative study employing dimer-specific ELISAs, Klein et al. reported that higher early follicular phase FSH levels in a group of older, ovulatory women (aged 40–45 yr) were associated with significantly lower mean inhibin B concentrations compared to those in younger cycling controls (38). The decrease in inhibin B levels demonstrated in these women of advanced reproductive age most likely reflects the presence of a diminished follicular pool. The association between decreased inhibin B and elevated FSH concentrations suggests that inhibin B may be an important regulator of the monotropic FSH rise that occurs with aging as well as a biochemical index of preantral follicles. This concept of inhibin B acting as a marker of reproductive age is supported by recent data indicating that women with low day 3 serum inhibin B levels demonstrate a poorer response to ovulation induction and are less likely to conceive a clinical pregnancy through assisted reproductive technology than women with high day 3 inhibin B levels (39). Although Klein et al. observed no difference in the day 3 inhibin A levels between older and younger women (38), other studies have demonstrated that the capacity of luteinized granulosa cells in culture to produce inhibin A was significantly lower in women with high FSH levels (40). Taken together, these data suggest that inhibin B levels reflect the number of follicles present, whereas inhibin A may be a marker of the quality of a mature follicle.

Experimental studies.

Response to GnRH analog: Children with CPP, before treatment and during GnRH agonist (GnRHa) therapy, provide a useful model of pubertal physiology in which to examine the differential regulation of gonadotropin secretion. In a study of girls with CPP, we have previously shown inhibin B levels to approximate those of women in the follicular phase, whereas inhibin A levels were at the limit of assay detection, suggesting that inhibin B is the predominant nonsteroidal modulator of FSH secretion during human female puberty (41). Treatment with GnRHa was associated with a significant fall in inhibin B to near undetectable levels in most patients, with values returning to baseline by 6 months off therapy. The response to reversible pituitary-gonadal suppression induced by GnRHa administration provides convincing evidence that inhibin B secretion during female puberty is dynamically regulated by gonadotropin stimulation of the ovary.

Response to gonadotropin stimulation: Several studies have reported an increase in total immunoreactive inhibin levels after the administration of exogenous gonadotropins for ovulation induction (37). These studies have noted a correlation between the inhibin response and the number of follicles stimulated as well as a decline in the inhibin response with increasing reproductive age. More detailed information has come from studies employing pituitary down-regulation with a GnRHa before stimulation with recombinant FSH for in vitro fertilization (IVF), as this regimen creates a hormonal milieu that allows the impact of high doses of FSH on ovarian inhibin secretion to be selectively elucidated. In a study of women with normal ovarian function participating in such an IVF treatment protocol, Lockwood et al. (42) demonstrated that both inhibin A and inhibin B were significantly suppressed in association with pituitary desensitization, whereas levels of pro-{alpha}-C were largely unaltered. Levels of both inhibins rose markedly during stimulation with FSH. The positive correlation observed between inhibin A levels in the late follicular phase and the number of follicles larger than 10 mm suggests that inhibin A may be useful as a marker of dominant follicle development in IVF. These data indicate that ovarian production of dimeric inhibin A and inhibin B in women is gonadotropin-dependent, whereas the regulation of pro-{alpha}-C may have a significant gonadotropin-independent component, consistent with our report of extragonadal production of pro-{alpha}-C in the male (11).

Control of inhibin B by FSH in GnRH-deficient women: In the intact model it is difficult to distinguish the relationship between inhibin and FSH, as gonadotropin stimulation is known to stimulate inhibin secretion, which, in turn, exerts a negative feedback on FSH. We, therefore, chose the model of GnRH-deficient women to explore the relationship between FSH and inhibin B secretion during the luteal-follicular transition by manipulating FSH levels via changes in the frequency of exogenous GnRH administration (34). The GnRH pulse frequency was either increased from every 4 h in the late luteal phase to every 90 min on the day of menses to mimic normal cycling women, or it was kept constant at a late luteal phase frequency through the first 6 days of the subsequent cycle. The slower rate of rise in FSH observed in the group in whom the GnRH pulse frequency was maintained at the slow luteal phase frequency was associated with significantly lower inhibin B levels in the early follicular phase, suggesting that there may be a critical rate of rise in FSH required for inhibin B stimulation (Fig. 5Go). In these studies the difference in the inhibin B responses to varying FSH levels was evident before changes were apparent in estradiol, indicating that inhibin B may be an important early prognostic indicator of follicular response during ovulation induction therapy.



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Figure 5. Impact of alterations in GnRH pulse frequency on FSH and inhibin B secretion during the luteal-follicular transition in GnRH-deficient women. Mean ± SEM levels of both FSH (•) and inhibin B ({blacksquare}) rose in association with an increase in the frequency of GnRH administration at the time of menses to mimic the GnRH frequency changes in the normal cycle. A more gradual rise in FSH ({circ}) was not associated with an increase in inhibin B ({square}) when GnRH administration remained at the slow luteal phase pulse frequency. *, P < 0.05; **, P < 0.02 (for comparisons between the two groups by repeated measures ANOVA on days 1–6). This was adapted with permission from the authors (34).

 
Response to gonadotropin suppression with a GnRH antagonist: A number of experiments employing GnRH antagonists have demonstrated the gonadotropin dependence of inhibin, as measured by the Monash RIA (see Ref. 43 for review). When ovulation was inhibited in macaques by administering a GnRH antagonist in the early follicular phase, the midcycle rise in inhibin levels failed to occur. Similarly, administration of a GnRH antagonist to normal women in the midluteal phase resulted in a sustained decline in serum inhibin concentrations that could be prevented by the concomitant administration of hCG, but not FSH (44), indicating that the luteal phase secretion of inhibin A is integrated with the LH control of the corpus luteum.

Effects of inhibin administration: Administration of recombinant inhibin A to subhuman primates during the luteal phase prevents the rise in FSH generally associated with the demise of the corpus luteum, whereas administration in the early follicular phase causes a progressive decrease in FSH levels (see Ref. 34 for review). These data provide more direct evidence for an endocrine role of inhibin A in the negative feedback regulation of gonadotropin secretion, which is consistent with the inverse relationship observed between inhibin A and FSH across the luteal-follicular transition.

Summary of inhibin physiology in the female: Inhibin A and inhibin B are differentially secreted in normal women, changing as a function of ovarian follicular development and possibly acting in a negative feedback mode to modulate FSH secretion. Inhibin A is a marker of the mature follicle and the corpus luteum, and may have an endocrine role in the luteal-follicular transition where a fall in inhibin A levels permits a rise in FSH to occur. Inhibin B secretion is stimulated by FSH, and data from older cycling women suggest that it may play an endocrine role in FSH secretion, although there is as yet no clear evidence that it contributes to the dynamic changes in FSH within a cycle.

Comparison of inhibin physiology in the male and female. In the human there appear to be important gender differences not only in the forms of inhibin present in the circulation, but also in their regulation by gonadotropins. Although both inhibin A and inhibin B are present in the female, only inhibin B circulates in physiological concentrations in the male. In addition, there is evidence for a gonadotropin-independent component to inhibin B secretion in males, but not in females. For example, in children with CPP treated with a GnRH analog, inhibin B levels in boys remain easily detectable, whereas in girls they are completely suppressed despite a similar degree of gonadotropin inhibition in both groups. Therefore, it appears that in the male, inhibin B secretion persists even after gonadotropin stimulation has been withdrawn unless there is a primary testicular defect. In the female, on the other hand, inhibin levels respond rapidly to gonadotropin changes throughout the menstrual cycle, with inhibin A and inhibin B falling to near-undetectable levels during the follicular and luteal phases, respectively. The mechanism for this differential regulation in the male and female gonad is not known. It may relate to tissue-specific regulation of {alpha}- and ß-subunit gene expression, or it may reflect fundamental differences in the relevant cell types in the testis and ovary. The presence of Sertoli cells is a consistent feature of the seminiferous tubule after early testicular development. In contrast, the highly coordinated maturation and atresia of ovarian follicles involves dynamic changes in the cell populations involved in inhibin synthesis and secretion. Further studies are required to address this issue.

Summary

Although considerable strides have been made in charting the physiology and pathophysiology of inhibin in the human, further progress awaits the development of recombinant inhibin suitable for administration in human studies. Measurements of total serum inhibin, although inadequate to chart the dynamic changes associated with normal and disordered pituitary-gonadal function, have proven to be of value as indices of ovarian tumor activity. Although the roles of specific dimeric inhibin measurements in clinical practice have not been clearly established, advances in our understanding of inhibin physiology and pathophysiology in the human suggest that inhibin B may have value as a marker of Sertoli cell function in men with infertility and as a prognostic indicator in women undergoing ovulation induction therapy.


    Acknowledgments
 
We gratefully acknowledge the helpful comments of Drs. Alan Schneyer and Corrine Welt during the preparation of this manuscript.


    Footnotes
 
1 This work was supported in part by Grants HD-15080, HD-15788, HD-18169, and RR-01066; the National Center for Infertility Research (U54-HD-29164); and the Reproductive Endocrine Sciences Center (P30-HD-28138) at Massachusetts General Hospital and Harvard Medical School. Back

Received December 18, 1997.

Revised February 17, 1998.

Accepted February 27, 1998.


    References
 Top
 Introduction
 The inhibin hypothesis
 Difficulties in charting inhibin...
 Inhibin physiology in the...
 References
 

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