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PubMed2002

Stimulation and growth of antral ovarian follicles by selective LH activity administration in women.

Intensive FSH stimulation is a key tool of assisted reproduction technology but can cause severe complications through the development of an excessive number of small ovarian follicles. We tested the hypothesis that, in the late stages of ovulation induction, LH activity in the form of low-dose human CG (hCG) can stimulate and selectively modulate ovarian follicle function and growth, independently of FSH administration. Four groups of GnRH agonist-suppressed normoovulatory women (10 each group) received recombinant human FSH (r-hFSH) (150 IU/d) for 7 d followed by: group A, r-hFSH 150 IU/d alone; group B, r-hFSH 50 IU/d and hCG 50 IU/d; group C, r-hFSH 25 IU/d and hCG 100 IU/d; group D, hCG 200 IU/d alone. Despite several days of lowered or absent r-hFSH administration, 70% of hCG-treated patients successfully completed treatment. In these subjects, preovulatory E2 levels and large (>14 mm diameter) ovarian follicle development were not reduced; conversely, the number of small (<10 mm diameter) ovarian follicles was significantly decreased in groups B-D vs. group A. Low-dose hCG administration did not cause follicle luteinization. We conclude that, following FSH priming, LH activity administration can: 1) stimulate folliculogenesis for several days, in spite of rapidly declining FSH levels; and 2) hasten small follicle demise. Therefore, LH activity administration could be used to design radically novel ovulation induction regimens that, by partly or completely replacing mid-/late follicular phase FSH administration, may reduce costs and improve safety of assisted reproduction technology.

Adult↗
PubMed1998

The follicle-stimulating hormone (FSH) threshold/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration, rather than magnitude, of FSH increase affects follicle development.

According to the threshold concept, FSH concentrations need to surpass a distinct level to stimulate ovarian follicle growth. The window concept stresses the significance of a limited duration of elevated FSH levels above the threshold for single dominant follicle selection. The aim of this study was to investigate effects on follicle growth of increased FSH levels, differing in duration and magnitude of elevation, during the follicular phase. Twenty-three normo-ovulatory (cycle length, 26-31 days), young (age, 20-31 yr) women volunteered for this study. In all subjects a series of daily transvaginal sonography scans of the ovaries and blood sampling [for FSH and estradiol (E2) determinations] were performed during two consecutive cycles. The first study cycle (control cycle) started 10 days after urinary assessment of the LH surge in the preceding cycle (DayLH) and was concluded on the day of ovulation assessed by transvaginal sonography scans. The second series of daily monitoring (intervention cycle) started 10 days after DayLH in the control cycle. After randomization, subjects received either 375 IU urinary FSH, s.c., as a single injection on Day(LH+14) (group A; n = 11) or 75 IU daily from Day(LH+19) until Day(LH+23) (group B; n = 12). In group A, FSH levels increased on the day after injection to a median concentration of 10.1 IU/L, which was 1.9 times higher (P < 0.01) than levels on matching days during the control cycle. Concentrations returned to basal levels 3 days after injection. In group B, a moderate elevation of FSH concentrations (15% increase; P < 0.05) was observed compared to levels during the control cycle. In group A, E2 concentrations increased (P = 0.03) 1 day after FSH injection and returned to baseline levels within 2 days. In group B, E2 levels started to increase after the first injection of FSH and remained significantly higher (P < 0.01) during the following 5 days compared to those on matching days in the control cycle. Compared to matching days in the control cycle an increased number of follicles 8-10 mm in size was found in group A (P < 0.01) during the period from Day(LH+14) until Day(LH+19), without an increase in follicles 10 mm or larger thereafter. In contrast, in group B, the numbers of both 8- to 10-mm and 10-mm or larger follicles were higher during the period from Day(LH+19) until Day(LH+24) in group B (P = 0.02 and P < 0.01, respectively). Results from the present study suggest that a brief, but distinct, elevation of FSH levels above the threshold in the early follicular phase does not affect dominant follicle development, although the number of small antral follicles did increase. In contrast, a moderate, but continued, elevation of FSH levels during the mid to late follicular phase (effectively preventing decremental FSH concentrations) does interfere with single dominant follicle selection and induces ongoing growth of multiple follicles. These findings substantiate the FSH window concept and support the idea of enhanced sensitivity of more mature follicles for stimulation by FSH. These results may provide the basis for further investigation regarding ovulation induction treatment regimens with reduced complication rates due to overstimulation.

Adult↗
PubMed1995

Selection of follicles, preculture oocyte evaluation, and duration of culture for in vitro maturation of equine oocytes.

Equine oocytes (n = 537) were collected from slaughterhouse ovaries (n = 118 mares) by scraping the internal follicular wall. Preculture record was made of the appearance of oocyte investments (no cumulus, corona radiata only, compact cumulus, expanded cumulus), appearance of cytoplasm (homogeneous, condensed heterogeneous/fragmented), and nuclear maturation stages (germinal vesicle, germinal-vesicle breakdown, metaphase I, metaphase II, degenerated). There was no difference between follicles > 30 mm and follicles < or = 30 mm in the preculture frequency distribution among the 5 nuclear stages; 96% were at either the germinal vesicle or germinal-vesicle breakdown stages. Oocytes from follicles 5 to 30 mm were cultured in modified TCM-199 for 18, 24, 36 and 48 h. Postculture nuclear maturation classifications were immature (germinal vesicle, germinal-vesicle breakdown, and metaphase I), mature (metaphase II or secondary oocyte), and degenerated. The frequency distribution of oocytes among the 3 postculture maturation classifications changed (P < 0.05) at 18 h (15% mature oocytes), changed (P < 0.05) further at 24 h (55% mature oocytes), with no additional change for 36 or 48 h. The only preculture cytoplasm group that affected the postculture results was the heterogeneous/fragmentation group which had a high proportion of postculture degenerated oocytes (67%); however, only 4% of oocytes were in this group. Luteal status of the mare had an effect (P < 0.05) on the frequencies of the maturation classifications, but not enough to be useful in selecting oocytes. Consistency of the follicle and the type of oocyte investment did not alter significantly the maturation frequencies. The frequency of degenerated oocytes after culture was high under the following conditions: 1) diameter of the follicle from which the oocyte was selected was 5 to 10 mm (44% degenerated oocytes), 2) the largest follicle per pair of ovaries was < or = 10 mm (63%), and 3) the mare was pregnant (66%). These results were probably related to the reported high frequency of atretic follicles in the 5- to 10-mm population. In summary, oocytes from individual follicles < or = 10 mm or from follicles in which the largest follicle per mare was < or = 10 mm were the poorest candidates for in vitro maturation.

Journal Article↗
PubMed2002

Lamprey gonadotropin hormone-releasing hormone-III has no selective follicle-stimulating hormone-releasing effect in rats.

Lamprey gonadotropin releasing-hormone (LGnRH)-III, a hypothalamic neurohormone recently isolated from sea lamprey, was reported to have a selective stimulatory effect on follicle-stimulating hormone (FSH) release in rats and suggested to be the mammalian FSH-releasing factor. In this study, we determined the relative luteinizing hormone (LH)- and FSH-releasing potency of LGnRH-III compared to mammalian gonadotropin-releasing hormone (LHRH) in normal female rats, ovariectomized (OVX) and oestrogen/progesterone substituted rats and the superfused rat-pituitary cell system. The specificity of LGnRH-III for the mammalian LHRH receptor was investigated by blocking the receptor with an LHRH antagonist, MI-1544. In vitro, LGnRH-III dose-dependently stimulated both LH and FSH secretion from rat pituitary cells at 10(-7) to 10(-5) M concentrations, while LHRH stimulated gonadotropin secretion at a 1000-fold lower doses (10(-10) to 10(-8) M). The difference between its LH- and FSH-releasing potency was similar to that of LHRH. LGnRH-III bound to high affinity binding sites on rat pituitary cells with a Kd of 6.7 nM, B(max)=113 +/- 27 fmol/mg protein. In vivo, LGnRH-III also stimulated both LH and FSH secretion in a dose-dependent manner and, similar to LHRH, induced a greater rise in the serum LH than the FSH level. In normal cycling rats, it showed 180-650-fold weaker potency than LHRH in stimulating LH secretion and 70-80-fold weaker effect in stimulating FSH secretion. In OVX rats, LGnRH-III demonstrated a similarly weak effect on both gonadotropins. It was found to be 40-210-fold less potent than LHRH regarding LH release and 50-160-fold weaker regarding FSH release. LHRH-receptor antagonist MI-1544 prevented both the LH- and the FSH-releasing effect of LGnRH-III both in vitro and in vivo. These results do not support the hypothesis that LGnRH-III might be the mammalian FSH-releasing factor but demonstrate that it is a weak agonist for the pituitary LHRH receptor and stimulates both gonadotropins in a dose-dependent fashion.

Animals↗
PubMedDate not supplied

The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest.

This review exposes the follicular abnormalities responsible for anovulation in polycystic ovary syndrome (PCOS). The putative pathophysiological explanations involve the principal intra- and extra-ovarian regulators which intervene during normal folliculogenesis to control the initial recruitment and growth and then the cyclic recruitment. We propose the hypothesis that the follicular problem in PCOS is 2-fold, but with the two abnormalities being linked. First, the intra-ovarian hyperandrogenism may promote early follicular growth, leading to a 2-5 mm follicle excess. Second, the ensuing excessive number of selectable follicles would inhibit the selection process, presumably through follicle-follicle interaction involving granulosa cell (GC) products such as the anti-Müllerian hormone (AMH). These factors would induce a reversible refractoriness to the FSH-induced differentiation of GC. This explanation challenges but does not exclude other hypotheses about the follicular arrest, such as the premature LH action on the GC of selectable follicles. Hyperinsulinism or insulin resistance would act as a second hit, worsening the follicular arrest either through amplification of the intra-ovarian hyperandrogenism or through dysregulation of the GC. The loss of cyclic rhythm would prevent the inter-cycle elevation of FSH, thus perpetuating the impairment of the ovulation process.

Androgens↗
PubMed2004

[Coordination of follicle antrum: from luteal estradiol to the premenstrual antagonist].

The foremost objective of controlled ovarian hyperstimulation (COH) is to ensure the adequate functional and morphologic maturation of early antral follicles to increase the number of viable oocytes and the probability of conception. One of the key points of such a procedure is the achievement of adequate synchronization of follicular growth so that ovulation can be triggered when most follicles have reached concomitant maturation. However, to obtain a good follicular coordination during COH, the physiological heterogeneity of selectable follicles observed during the early follicular phase should probably be overcome. Luteal E2 administration reduces size discrepancies of early antral follicles during the early follicular phase. This approach constitutes a simple and promising method to foster follicular growth synchronization during COH. Luteal GnRH antagonist reduces the mean antral follicle size and reduces heterogeneity of selectable follicles. If these results are confirmed, the luteal administration of E2 or GnRH antagonists represents a potential, more physiological alternative to GnRH agonist or oral contraceptive pretreatment.

Anovulation↗
PubMed2002

Relationship between steroidogenic acute regulatory protein expression and progesterone production in hen granulosa cells during follicle development.

The present studies were conducted to address cellular mechanisms responsible for regulating steroidogenic acute regulatory protein (StAR) expression and progesterone synthesis at maturational stages corresponding to both the time of hen follicle selection, as well as before and after the LH surge in preovulatory follicle granulosa cells. A recently published report has established that mitogen-activated protein (MAP) kinase signaling induced by transforming growth factor alpha (TGFalpha) treatment blocks FSH-induced differentiation and StAR expression in cultured hen granulosa cells, whereas inhibitors of MAP kinase signaling enhance FSH-induced differentiation. The present in vitro studies demonstrate that in addition to MAP kinase signaling, activation of protein kinase C (PKC) blocks both FSH-induced StAR expression and the initiation of progesterone production in prehierarchal follicle granulosa cells, whereas the pharmacologic inhibitor of PKC, GF109203X, potentiates FSH-induced StAR expression and, as a consequence, the initiation of progesterone synthesis. Moreover, we demonstrate in granulosa cells collected from preovulatory follicles that although an acute increase in progesterone production in response to LH treatment requires rapid transcription and translation of StAR, the magnitude of progesterone production is rate-limited by one or more factors other than StAR (e.g., the P450 cholesterol side-chain enzyme). Finally, the rapid turnover of StAR protein, such as occurs following the withdrawal of LH, provides an additional mechanism for the tight regulation of progesterone production that occurs during the hen ovulatory cycle, and explains the rapid loss of steroidogenesis in the postovulatory follicle. In summary, data reported herein support the proposal that paracrine/autocrine factors (including but not necessarily limited to TGFalpha) prevent premature expression of StAR in prehierarchal follicle granulosa cells by more than one receptor-mediated signaling pathway. Furthermore, subsequent to follicle selection into the preovulatory hierarchy, StAR transcription and translation is necessary but not sufficient for the full potentiation of the preovulatory surge of serum progesterone.

Animals↗
PubMed2000

The reproductive pattern and efficiency of female buffaloes.

Buffaloes play a prominent role in rural livestock production, particularly in Asia. Reproductive efficiency is the primary factor affecting productivity and is hampered in female buffalo by (i) inherent late maturity, (ii) poor estrus expression in summer, (iii) distinct seasonal reproductive patterns, and (iv) prolonged intercalving intervals. Ovarian function is central to these issues; hence, the focal point of this review is ovarian function in Bubalus bubalis, particularly, in relation to seasonal changes. Ovarian anatomy, follicular and luteal development development, and hormonal profiles during the estrous cycle are discussed. Review of the literature revealed a paucity of critically derived information on follicular and ovulatory patterns in buffalo, particularly, in relation to seasonal estrus/birthing. Efforts may be directed at understanding the process (recruitment, development, atresia) and temporal pattern (follicle selection, dominance, subordinate follicle suppression, follicle numbers, and, preovulatory changes) of follicular dynamics using techniques which permit serial assessment of changes occurring over time. Emphasis may be directed towards investigating follicular "waves" as a functional unit, rather than the estrous cycle, in the context of whole animal endocrinology. The data obtained from such basic studies may then be used to develop and test models for enhancing reproductive efficiency.

Animals↗
PubMed2003

Proteolytic degradation of insulin-like growth factor binding proteins by ovarian follicles: a control mechanism for selection of dominant follicles.

This review summarizes evidence for the role of proteolytic enzymes that degrade and inactivate insulin-like growth factor binding proteins (IGFBP) during follicular development in mammals. In some species (e.g., bovine), evidence indicates that decreases in IGFBP-4 and -5 levels in estrogen-dominant preovulatory follicles are likely due, in part, to increased protease activity, whereas lower levels of IGFBP-2 are not due to increased proteolysis. Increased IGFBP-4 and -5 protease along with lower amounts of IGFBP-4 binding activity and greater amounts of free IGF-I are some of the earliest developmental changes documented in bovine growing antral follicles. This protease activity has recently been ascribed to serine metalloprotease(s), including pregnancy-associated plasma protein-A (PAPP-A), which was first detected in human follicular fluid nearly 20 yr ago. Other recent studies verified the presence of PAPP-A mRNA in granulosa cells of humans, monkeys, cattle, mice, and pigs. Increases in the amount of PAPP-A mRNA in granulosa cells during follicular development occurs in some but not all species, indicating that other proteases or protease inhibitors may be involved in IGFBP degradation. Whether the hormonal control of PAPP-A production/activity by the ovary differs between monotocous and polytocous animals will require further study. These protease-induced decreases in IGFBP-4 and -5 likely cause increased levels of bioavailable (or free) IGFs that stimulate steroidogenesis and mitogenesis in developing dominant follicles, which ultimately prepare the follicle(s) and oocyte(s) for successful ovulation and fertilization.

Animals↗
PubMedDate not supplied

Regulation of follicle development and novel approaches to ovarian stimulation for IVF.

Current ovarian stimulation regimens for IVF are complex and not without risk. Increasing our knowledge of the physiology of follicle development and dominant follicle selection may enable the design of less complex, safer and cheaper ovarian stimulation regimens for IVF. Decremental serum FSH concentrations during the follicular phase of the menstrual cycle are required for single dominant follicle selection. Only the most mature follicle will continue its development due to increased sensitivity for stimulation by FSH. FSH stimulation becomes insufficient for less mature follicles and remaining cohort follicles will therefore go into atresia. The number of days during which FSH is above the threshold for stimulation of follicle development is limited, resulting in a narrow FSH window. More medium sized and large pre-ovulatory follicles and increased oestradiol output can be induced by the administration of small doses of exogenous FSH during the mid- to late follicular phase, preventing the physiological decrease in FSH stimulation. Intervention with decremental serum FSH concentrations in combination with gonadotrophin-releasing hormone (GnRH) antagonists to prevent a premature rise in serum LH may induce ongoing growth of multiple follicles sufficient for IVF. The benefits and risks of these minimal hyperstimulation protocols require further evaluation.

Female↗
PubMed1994

Assessment of the presence of a dominant follicle and selection of dairy cows suitable for superovulation by a single ultrasound examination.

The physiological significance of the dominant follicle (> 9 mm in diameter in a growing phase; stable for < 3 days) for the superovulatory response in 117 lactating Holstein Friesian dairy cows was investigated. The presence or absence of a dominant follicle was determined retrospectively by analysing videotapes of follicular growth in all the ovaries. Superovulation was induced by 28 mg Armour units (400 mg NIH-FSH-P1) of FSH (Folltropin) administered either twice or once a day i.m. over 4 days in a decreasing regimen or as a single injection s.c. Donors were scanned daily from day 3 after the oestrus preceding superovulation until embryo recovery. In Expt 1 donors superovulated (two times a day for 4 days) in the absence of a dominant follicle yielded more corpora lutea (11.7 +/- 0.9 versus 4.7 +/- 1.1, P < 0.01), ova and embryos (8.2 +/- 1.2 versus 2.8 +/- 1.0, P < 0.01) and transferable embryos (5.0 +/- 1.0 versus 2.1 +/- 0.9, P < 0.05) compared with donors treated in the presence of a dominant follicle. In Expts 2 and 3 donors were scanned only on the day of superovulation and donors with < 10 follicles 3-8 mm in diameter were considered to have a dominant follicle, while donors with > or = 10 small follicles 3-8 mm in diameter were classified as having no dominant follicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Follicular development and ovulation in the marmoset monkey as determined by repeated laparoscopic examination.

This paper describes the course of follicular development in vivo in the marmoset monkey, the only anthropoid primate with a relatively high (2-4) and variable ovulation number. Results are presented in relation to predictions from a mathematical model of control of follicle selection and ovulation number. Repeated laparoscopic examinations during the follicular phase were conducted for 14 cycles. Ovulatory follicles were 1.0 mm (median) in diameter at Day 6 and could be distinguished from nonovulatory follicles by Day 8, at which point they were 2.0 mm in diameter. Ovulations were not synchronous; the most common observation 1-2 days after the estradiol peak was ovulation of one follicle but not the other. Examination of the course of follicular development within a cycle and the distribution of ovulation sites both supported predictions stemming from a mathematical model of follicle selection developed by Lacker et al. [Biol Reprod 1987; 37:570-580]. Specific findings were the following: 1) Variations in patterns of follicle growth within a cycle resembled those generated by the model; in 64% of cycles, the 2-3 ovulatory follicles grew at similar rates. However, in 36% of cycles, ovulatory follicles displayed disparate rates of growth. 2) An examination of the distribution of ovulation sites (right versus left) revealed no significant difference from a binomial distribution, suggesting the likelihood that interovarian (rather than intraovarian) factors control this distribution.

Animals↗
PubMed1982

Follicle dominance and ovarian asymmetry after luteectomy in rhesus monkeys.

Previous work demonstrated that asymmetrical ovarian activity accompanies morphological asymmetry during the ovarian cycle in rhesus and cynomolgus macaques. This study was designed to determine whether functional ovarian asymmetry could be used to detect the upcoming dominant follicle (DF) even before it was grossly visible. Revealing a latent DF in this manner would permit a better estimate of the time when dominance of the follicle selected to ovulate is attained. To accomplish this, rhesus monkeys were luteectomized at midluteal phase to synchronize subsequent follicle growth, and 4 or 8 days later either the ipsilateral or contralateral ovary was removed. Unilateral ablation at day 4 (when no DF is grossly apparent) of either ovary produced symmetrical responses: the interval from luteectomy (CLX) to the next luteinizing hormone (LH) surge was extended by about 4 days in both groups (P less than 0.01), i.e., from about 12.5 days to 16.7 +/- 1.6 and 17.0 +/- 1.5 days (mean +/- SE). In contrast, hemiovariectomy at day 8 produced markedly divergent asymmetrical responses. Removal of the ipsilateral ovary 8 days after CLX did not affect the timing of the next LH surge (13.2 +/- 0.6 days), which ordinarily occurs about 12.5 days after CLX alone. However, ablation of the contralateral ovary (bearing the next DF) on day 8 extended the interval from CLX to the next LH surge from about 12.5 to 26.6 +/- 1.3 days. These findings indicate that, during the normal ovarian cycle when menses occurs 2--4 days after luteolysis, the follicle destined to ovulate becomes dominant between the 2nd and 6th day and that attainment of dominance signals the completion of a follicle selection process that begins or resumes promptly after luteolysis.

Animals↗
PubMed1989

Basal gonadotropin hormone release rates during the period of selective follicle-stimulating hormone release in the juvenile female rat.

There are situations in which adult female rats release increased amounts of follicle-stimulating hormone (FSH) independent of increased luteinizing hormone (LH) release. This results from, at least in part, a selective increase in the basal FSH release rate. We investigated whether an increase in the basal FSH release rate is contributory to the rise in serum FSH levels which occurs independent of a rise in serum LH levels in the immature female rat. Rats had high serum FSH concentrations on days 7 and 15 after birth, low serum FSH levels on day 23, and low serum LH levels on all three days. In contrast, anterior pituitary gland (APG) FSH and LH concentrations and contents increased from day 7 to day 15 and the contents increased further from day 15 to day 23. Similarly, basal FSH and LH release rates per mg APG or per APG, as assessed by measurement of FSH and LH released into culture medium containing APG(s) from different aged rats, increased from day 7 to day 15 but did not increase further between days 15 and 23. The results indicate that unlike situations observed to date in adult female rats, a mechanism(s) other than an increase in the basal FSH release rate is involved in selective FSH release in the immature female rat.

Aging↗
PubMed1996

Induction of apoptotic cell death in hen granulosa cells by ceramide.

Recent studies have demonstrated that ovarian follicle atresia occurs extensively before follicle selection into the avian preovulatory hierarchy, and that this process is mediated via granulosa cell apoptosis. Subsequent to follicle selection, granulosa cells are inherently resistant to apoptosis, and such resistance is correlated with increased expression of death suppressor genes such as bcl-xlong. In the present studies we used this avian ovary model system to 1) identify cellular characteristics and mechanisms related to apoptotic cell death of granulosa cells in vitro, and 2) further characterize functional differences between apoptosis-susceptible (4- to 8-mm follicle) and apoptosis-resistant (preovulatory follicle) granulosa cells. Treatment of granulosa cells from the largest preovulatory follicle with N-octanoylsphingosine (C8-ceramide) results in pronounced oligonucleosome formation, a hallmark of apoptosis. That this is indicative of programmed cell death is supported by an increased incidence of pyknotic nuclei and apoptotic bodies in C8-ceramide-treated samples compared to that in control cultured cells. Tumor necrosis factor-alpha, a stimulator of ceramide production, actively promotes oligonucleosome formation in apoptosis-susceptible, but not in apoptosis-resistant, granulosa cells. Induction of apoptosis is also observed after exposure of apoptosis-resistant granulosa cells to sphingomyelinase treatment and UV irradiation, which are known to stimulate endogenous ceramide production, and to the anticancer drug, daunorubicin, which initiates de novo ceramide biosynthesis via activation of ceramide synthase. Although treatment of granulosa cells with fumonisin B1, a specific ceramide synthase inhibitor, blocks daunorubicin-stimulated oligonucleosome formation, UV-induced cell death is unaffected. Taken together, these results demonstrate that pharmacological factors known to mimic the actions of ceramide or stimulate ceramide production can induce oligonucleosome formation and programmed cell death in granulosa cells. More importantly, however, the ability of a physiologically relevant initiator of ceramide biosynthesis, tumor necrosis factor-alpha, to promote cell death is evident only in apoptosis-susceptible granulosa cells collected from atresia-prone prehierarchal follicles. These data provide support for ceramide as an important intracellular signaling mechanism, mediating granulosa cell apoptosis and follicle atresia.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1989

Regulation of testicular inhibin subunit messenger ribonucleic acid levels in vivo: effects of hypophysectomy and selective follicle-stimulating hormone replacement.

To examine the pretranslational regulation of inhibin subunits in the rat testis by FSH, we studied the effects of hypophysectomy with or without selective FSH replacement on testicular inhibin subunit mRNA levels in immature and adult animals. In the first experiment (Exp I), sexually immature (20-23 days old) intact and hypophysectomized male rats were killed 1, 3, and 7 days after surgery, and the testicular content of inhibin subunit mRNAs was determined by filter hybridization. A second group of immature, intact, or hypophysectomized rats was treated with saline or FSH for 7 days as follows: I) intact, saline; II) hypophysectomized, saline; III) hypophysectomized, FSH [0.05 microgram/100 g BW, sc, twice daily (BID)]; IV) hypophysectomized, FSH (0.50 microgram/100 g BW, sc, BID); V) hypophysectomized, FSH (5.0 micrograms/100 g BW, sc, BID); and VI) hypophysectomized, FSH (50.0 micrograms/100 g BW, sc, BID). In the second experiment (Exp II), adult (60 days old) intact or hypophysectomized animals were treated with saline, FSH, and/or testosterone for 7 days as follows: I) intact, saline; II) hypophysectomized; saline; III) hypophysectomized, 22-mm testosterone implant; IV) hypophysectomized, FSH (50.0 micrograms/100 g BW, sc, BID; and V) hypophysectomized, 22-mm testosterone implant plus FSH (50.0 micrograms/100 g BW, sc, BID. The effects of FSH and testosterone on testicular inhibin subunit mRNA levels were measured by filter hybridization. In Exp I, the level of inhibin alpha-subunit mRNA per testis was significantly lower in hypophysectomized rats than in intact controls at all time points after surgery. Replacement of FSH to hypophysectomized immature rats led to a dose-dependent increase in alpha-subunit mRNA per testis. However, hypophysectomy and FSH replacement had no significant effect on beta-B-subunit mRNA. In adult rats (Exp II), hypophysectomy significantly lowered and FSH replacement increased testicular inhibin alpha-subunit mRNA levels. Replacement of testosterone to adult animals, either alone or in combination with FSH, had no effect on expression of inhibin alpha-subunit mRNA. beta-B mRNA levels in adult testis were not significantly altered by any of the treatments. beta-A-Subunit mRNA levels were below the detection threshold of filter hybridization in both Exp I and II. Collectively, these data demonstrate that FSH regulates alpha- but not beta-B-subunit mRNA in the testis of both immature and adult rats in vivo. Differential regulation of inhibin subunits may provide a mechanism for creation and regulation of functional diversity of inhibin-related peptides in the testis.

Animals↗
PubMed2005

Clinical and hormonal features of selective follicle-stimulating hormone (FSH) deficiency due to FSH beta-subunit gene mutations in both sexes.

OBJECTIVE: To report the clinical, hormonal, and molecular features of a female adolescent with selective FSH deficiency. In addition, a complete review of previous cases is provided, focusing on hormonal aspects. DESIGN: Clinical study. SETTING: University hospital. PATIENT(S): A 16-year-old girl with primary amenorrhea and poor breast development due to isolated FSH deficiency. INTERVENTION(S): Blood drawing before and after GnRH stimulation and pelvic ultrasound examination. MAIN OUTCOME MEASURE(S): Gonadotropin and E(2) measurements and sequencing of the FSH beta-subunit gene. RESULT(S): The patient was referred for primary amenorrhea and partial breast development (Tanner III). Her basal and GnRH-stimulated LH levels were elevated (31 IU/L and 98 IU/L, respectively), whereas her FSH levels were undetectable (<1 IU/L) in both conditions. Estradiol levels were low (<13 pg/mL). Automatic sequencing showed a nucleotide substitution of C for A in exon 3, resulting in a homozygous nonsense mutation in amino acid position 76 (Tyr76X) of the FSH beta-subunit. CONCLUSION(S): The Tyr76X mutation of the FSH beta-subunit was associated with a partial phenotype of FSH deficiency. To date, only four loss-of-function mutations of the FSH beta-subunit have been described in eight patients with undetectable serum FSH and high serum LH levels. Therefore, this unusual hormonal profile strongly suggests a defect in the FSH beta-subunit in both sexes.

Adolescent↗
PubMed2001

Lamprey gonadotropin-releasing hormone-III selectively releases follicle stimulating hormone in the bovine.

Recent studies have shown that lamprey gonadotropin-releasing hormone (l-GnRH) is localized in the mammalian brain, and that l-GnRH-III, can selectively induce FSH secretion in the rat both in vivo and in vitro. Consequently, the purpose of this study was to determine if l-GnRH-III could elicit selective FSH release in cattle and compare this response with that to mammalian luteinizing hormone releasing hormone (m-LHRH). Cattle were chosen as the animal model because previous studies have demonstrated that FSH and LH are secreted by separate gonadotropes in that species. For these studies, crossbred cycling heifers were implanted with jugular cannulae and l-GnRH-III was infused either between Days 9-14 or on Day 20 of the estrous cycle. Blood samples were collected both before and following peptide infusion. Our results demonstrate that during Days 9-14 of the estrous cycle (luteal phase), when progesterone levels averaged between 4 and 5 ng/ml, a dose of 0.25 mg of l-GnRH-III induced the release of FSH (P < 0.05), but not LH. A 0.5 mg dose of l-GnRH-III caused a greater release of FSH (P < 0.01), but still did not induce LH release. Higher doses of the peptide were capable of significantly releasing both gonadotropins. Importantly, during the luteal phase, doses of 0.5 and 2 mg of m-LHRH were ineffective in stimulating FSH, but did elicit marked increases (P < 0.001) in LH. Again, progesterone levels averaged 4-5 pg/ml. In order to assess gonadotropin releasing ability of l-GnRH-III at a different phase of the estrous cycle, some animals were administered the peptide on Day 20, when progesterone levels were below 1.0 pg/ml. At this time, the l-GnRH-III induced the release of LH (P < 0.01), but not FSH. Overall, our results demonstrate that l-GnRH-III can selectively induce FSH in cattle during the luteal phase, whereas m-LHRH was ineffective in that regard. Furthermore, the fact that l-GnRH-III can selectively stimulate FSH when serum progesterone is high, and LH when serum progesterone is low, suggests its actions are under strong control of this steroid. We suggest the FSH releasing capacity of l-GnRH-III in cattle could render this peptide useful for enhancement of reproductive efficiency in this species.

Animals↗