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Andrology Laboratory, ANZAC Research Institute, University of Sydney, Concord Hospital, New South Wales 2139, Australia
1 Department of Reproductive Medicine, Westmead Hospital, University of Sydney, New South Wales 2145, Australia
(Requests for offprints should be addressed to C M Allan; Email: charles{at}anzac.edu.au)
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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While small preantral follicular development may occur independently of FSH, the total number of early growing follicles is increased by FSH action (Halpin & Charlton 1988, McGee et al. 1997, Oktay et al. 1998). Furthermore, FSH-mediated follicle growth may also indirectly accelerate the age-dependent depletion of the finite primordial pool initially established after birth. For example, increased basal serum FSH in young adult rats after unilateral ovariectomy is associated with an increased loss of primordial follicles (Meredith et al. 1992, Anzalone et al. 2001). Advancing our understanding of FSH effects on ovarian development and its capacity to regulate early folliculogenesis has implications for follicle preservation and/or recovery during or after chemotherapy (Blumenfeld 2002) or in vitro fertilization (IVF) treatment (Huirne et al. 2004), or for the relationship between elevated FSH and follicle depletion during human reproductive ageing (Hansen et al. 2005), particularly in light of the potential for sustained primordial follicle renewal throughout life (Johnson et al. 2004). However, investigating the direct, selective in vivo effects of FSH in the ovary is difficult in human subjects, while suitable animal models are limited.
For selective examination of gonadal FSH actions, we previously generated transgenic (tg) mice that express human FSH independently of GnRH (Allan et al. 2001). This features pituitary-independent tg-FSH expression, which, when combined with the gonadotrophin-deficient background of hypogonadal (hpg) mice, allows investigation of FSH activity in isolation of LH effects (Allan et al. 2001, 2004). The hpg mouse is complementary to models with selective disruption of LH-beta (Ma et al. 2004) or receptor (Lei et al. 2001, Zhang et al. 2001) genes, although free from secondary effects on FSH secretion that confound interpretation of the later model of permanent LH insensitivity. The immature ovaries of hpg females exhibit follicle arrest at the preantral stage but remain hormonally responsive (Halpin et al. 1986, Allan et al. 2001). We previously showed that tg-FSH dose-dependently increased ovary weights and circulating inhibin B levels in hpg mice (Allan et al. 2001). This tg-FSH hpg paradigm is now used to explore the effect of FSH upon follicle dynamics in young, mature females, revealing unexpected upregulation by FSH of the primordial follicle stock.
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Materials and Methods |
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Transgenic 
ß.6 mice expressing human (h)FSH (tg-FSH) independently of GnRH were previously described (Allan et al. 2001). Females expressing tg-FSH on a gonadotrophin-deficient hypogonadal background (Gnrh1–/–) were obtained by crossing tg animals heterozygous for the Gnrh1 gene deletion (Gnrh1+/–) as determined by detection of wild-type or disrupted Gnrh1 gene or tg PCR products, as previously described (Singh et al. 1995, Allan et al. 2001). Animals were housed under controlled conditions (12-h light–dark cycle, 19–22 °C) with free access to food and water. Mature mice (9–11 weeks old) were used for ovary collection. Littermates or age-matched non-tg Gnrh1–/–(denoted hpg) or wild-type (Gnrh1+/+ or Gnrh1+/–) females served as controls. Animal procedures were approved by the University of Sydney animal ethics committee and performed in accordance with the National Health and Medical Research Council Code of Practice for the Care and Use of Animals and the NSW Animal Research Act 1985. Blood was collected from terminally anaesthetized mature females, and serum was stored at –20 °C.
Serum hormone assays
Serum hormone levels were measured in duplicate in all assays. Serum levels of human FSH were determined by species-specific, two-site immunofluorometric assay as previously described (Allan et al. 2001). Inhibin A and B levels were determined with human inhibin assays and serially diluted mouse follicle culture media as standard (Wang et al. 2005). Inhibin levels were interpolated from mouse standards, using arbitrary units (AU/ml) to avoid non-parallelism between human standards and mouse samples (Wang et al. 2005). Detection limits for inhibin A and B were 7.8 and 8.0 AU/ml respectively.
Ovary fixation and follicle counting
Ovaries were removed and incubated overnight in 4% paraformaldehyde in PBS (pH 7.4), washed with 70% ethanol and then embedded in hydroxymethylmetha-crylate resin (Technovit 7100; Kulzer, Friedrichsdorf, Germany) as recommended by the manufacturer. With one ovary per mouse, tissue sections were cut with the Polycut S microtome (Reichert Jung, Nossloch, Germany). Thin sections (5 µm) were stained with 0.5% toluidine blue, and thick sections (25 µm) for follicle counting were consecutively stained with periodic acid-Schiff, haematoxylin and Scott’s blue solution. Morphological identification and estimation of total primordial (oocytes with partial or complete layer of squamous granulosa cells (Meredith et al. 2000)), primary (single layer of cuboidal granulosa cells), secondary (two or more layers of cuboidal granulosa cells but no visible antrum), or antral (one or multiple visible fluid filled antral cavities) follicles were performed with a light microscope with microcator to monitor section depth and CAST-GRID software (Olympus, Albertslund, Denmark). Follicle nuclei (primordial) or nucleoli (primary-antral) were used as reference counting points. In serial sections, the first sections were selected randomly, then all primordial and primary follicles were counted (x40 oil objective) to a depth of 18 µm in every fourth 25 µm section, and then whole ovary estimates were calculated by Cavalieri’s principle and accounting for section (x4/1) and depth (x25/18) sampling. Section areas flanking the 18 µm counting depth allowed confirmation of follicle classifica-tion (e.g. primordial vs primary) to avoid potential capping effects. Total secondary and antral follicle numbers were counted in every 25 µm serial section from each ovary (x10 objective).
Statistical analysis
Statistical analysis was performed with SigmaSat statistical software (SPSS Version 11.0; Chicago, IL, USA). Data were analysed by unpaired t-test, Fisher’s test, Pearson correlation or one-way ANOVA; significance (differ-ences, linear association) was defined as P < 0.05. Samples with undetectable hormones were assigned zero. Alternative assignment to detection limit values did not alter any significant difference observed. All data are presented as mean ± S.E.M.
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Results |
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Body weights of 9–11-week-old tg-FSH and non-tg hpg females were equivalent, but reduced (15–18%) in comparison to age-matched, non-tg, wild-type controls (Fig. 1
). Compared with hpg controls, the tg-FSH hpg females exhibited significantly increased ovary weights (fourfold), which remained threefold smaller than wild-type age-matched ovaries (Fig. 1).
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Qualitative histological examination of non-tg hpg ovaries from 9–11-week-old females showed follicular development progressed beyond primary follicle stage, and sparse numbers of early antral follicles were detected, as shown in Fig. 2. Examination of tg-FSH hpg ovaries revealed that follicular development had progressed to advanced antral stage, as Fig. 2 shows. No corpora lutea were observed in any tg-FSH or non-tg hpg ovary examined.
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Total primordial follicle numbers in 9–11-week-old tg-FSH hpg females were significantly higher (twofold, P < 0.05) than in both non-tg hpg and wild-type females. The total number of primordial follicles was equivalent in age-matched, gonadotrophin-deficient hpg relative to wild-type ovaries (Fig. 3). The absolute number of primary follicles in tg-FSH hpg ovaries was not signifi-cantly different from non-tg hpg or wild-type ovaries (Fig. 3). However, secondary follicles were significantly increased (P < 0.001) and restored to normal levels in tg-FSH hpg mice (Fig. 3), although the total number of secondary ovarian follicles in hpg mice was only 25% of wild-type numbers. Non-tg hpg control ovaries contained limited numbers of early antral follicles with small emerging antral spaces, and total antral follicle numbers of just 4.5% of wild-type numbers. Expression of tg-FSH signifi-cantly increased (P < 0.001) total antral follicles more than 15-fold compared with non-tg hpg controls, restoring numbers to wild-type levels (Fig. 3).
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Mature (9–11-week-old), transgenic, ß.6 line hpg females expressed serum hFSH levels of 5.4 ± 0.2 IU/l (n=14), whereas non-tg females had undetectable hFSH levels consistent with previous findings (Allan et al. 2001).
Serum inhibin B was detectable (
8.0 AU/ml) in significantly more tg-FSH (14/14) than non-tg (3/16) hpg females (P < 0.001, Fisher’s test), and tg-FSH hpg mice had significantly higher (P < 0.001) serum inhibin B levels (Fig. 4). There was no difference between serum inhibin B levels in tg-FSH hpg and mature, wild-type females. Furthermore, there was a significant correlation between inhibin B levels and secondary and antral follicle numbers in the tg and non-tg hpg ovaries examined, whereas there was no correlation with primordial and primary follicle numbers (Fig. 5). Partial regression showed that the strongest inhibin B relationship was with the antral follicles and that the relationship with secondary follicles was derived from that with antral follicles.
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7.8 AU/ml) in significantly more tg-FSH (10/14) than non-tg (2/16) hpg females (P < 0.005, Fisher’s test), and mean levels of serum inhibin A were significantly higher (P < 0.05) in the tg-FSH group (Fig. 4
). Serum inhibin A levels were lower in tg-FSH hpg than in mature, wild-type females, and there was no correlation between serum inhibin A and different follicle types present in the tg and non-tg hpg ovaries examined (data not shown). |
Discussion |
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Total primordial follicle numbers in tg-FSH hpg mice were also greater than the numbers in age-matched wild-type mice, suggesting that tg-FSH activity increased the overall development and/or survival of primordial follicles. The precise mechanism of the FSH-stimulated increase in total primordial follicles in tg hpg ovaries remains undefined, but may involve increased initial accrual, decreased atresia or reduced developmental progression of the primordial follicle population. The observation of equivalent numbers of primordial follicles in mature non-tg hpg and wild-type ovaries is consistent with an early report of similarly ‘non-growing’ follicle numbers in immature and adult hpg and wild-type mice (Halpin et al. 1986). Mouse primordial follicle numbers are maximal during early postnatal development (Peters 1969, Hirshfield 1991, Johnson et al. 2004) and thereafter rapidly decline via atresia (Faddy et al. 1983, 1987, McGee & Hsueh 2000). Therefore, the larger primordial pool in mature tg-FSH hpg ovaries relative to normal (or non-tg hpg) may reflect a reduced rate of atresia. Alternatively, the rate at which primordial follicles enter the growth phase may be reduced in tg hpg mice by the presence of more secondary/antral follicles (Faddy et al. 1987). However, we did not observe decreased numbers of downstream primary follicles in tg hpg ovaries compared with controls, consistent with studies in hpg females treated with exogenous FSH for 4–20 days (Halpin & Charlton 1988, Wang et al. 2005). Instead, primary follicle numbers were equivalent to controls, suggesting that reduced primordial recruitment may not explain our results.
Another possibility is that perinatal formation of the primordial population may be enhanced in tg-FSH hpg mice. Although this stage was considered FSH-independent due to minimal FSH binding (Dunkel et al. 1994) or responsiveness (Peters et al. 1973, Sokka & Huhtaniemi 1990) and absence of full-length FSH receptor mRNA (Dunkel et al. 1994, Rannikki et al. 1995, O’Shaughnessy et al. 1996) in perinatal mouse or rat ovaries, recent studies suggest that FSH activity may regulate early folliculogenesis before the arrival of later-stage, FSH-dependent growing antral follicles. In hamsters, an early role for FSH in folliculogenesis is suggested by reduced primordial follicle formation after treatment of mothers with FSH-antiserum during late gestation, and expression of full-length FSH receptor mRNA in the fetal ovary as early as day 13 of gestation (Roy & Albee 2000). Neonatal (2-day-old) mice genetically lacking functional FSH receptor exhibit reduced numbers of early, non-growing follicles (Balla et al. 2003). Furthermore, FSH receptor mRNA transcripts are present in 1–5- day-old mouse ovaries (O’Shaughnessy et al. 1996), 3-day-old rat ovaries (Dunkel et al. 1994) and human early preantral follicles (Oktay et al. 1997). Our data combined with the above observations challenge the view of gonadotrophin-independent early folliculogenesis and suggest that FSH activity can significantly influence the primordial and early preantral follicle populations. Whether or not tg-FSH in our model has direct effects on early follicles during (or after) primordial formation, or progressive indirect actions through the growing follicle populations over time remains to be determined. Future analysis of primordial follicle dynamics in postnatal and ageing tg hpg mice will enhance our understanding of this unexpected primordial follicular response to FSH.
In contrast to the normal primordial numbers found in hpg ovaries, hypophysectomized (Meredith et al. 1986) or GnRH-antagonist treated (Meijs-Roelofs et al. 1990) rats exhibit a decreased rate of loss of primordial follicles, resulting in higher than normal primordial follicle numbers. The different primordial numbers found in these gonadotrophin-deficient mouse and rat models remains an enigma. One notable difference between the hpg mouse and classical rat models is the delayed postnatal loss of gonadotrophins in 21-day-old hypophy-sectomized or 6–15-day-old GnRH-antagonist-treated rats, compared with congenital FSH/LH absence in hpg mice. Complete absence of postnatal FSH in hpg mice may account for the decreased primordial stock relative to the above rat models. In the present study, tg-FSH expression is driven by the rat insulin II gene promoter that confers postnatal expression of heterologous trans-genes (Epstein et al. 1992, Takamura et al. 1998), as confirmed by equivalent serum tg-FSH levels in 10-day-old mice (data not shown). Therefore, the tg-hpg model will provide FSH expression during the important post-natal period of follicular development, unlike previous studies of short-term exogenous FSH actions in hpg females only after complete postnatal gonadotrophin deficiency (Halpin & Charlton 1988, Wang et al. 2005).
Our tg-hpg model has provided direct evidence that FSH activity in the absence of LH may markedly affect the development, survival or recruitment of the early follicle population. Previous work showed that mice overexpress-ing tg LH exhibited an accelerated loss of primordial follicles despite the presence of FSH (Flaws et al. 1997). Therefore, increased numbers of primordial follicles in tg-FSH hpg females may also reflect the absence of an opposing LH effect on the resting primordial follicle pool. Despite the lack of LH activity in hpg ovaries, the expression of tg-FSH increased secondary and stimulated antral follicle development, confirming previous in vivo studies demonstrating that antral follicle development is highly regulated by FSH (Halpin & Charlton 1988, Wang & Greenwald 1993, Kumar et al. 1997, McGee et al. 1997, Dierich et al. 1998, Oktay et al. 1998, Abel et al. 2000).
Increased serum levels of inhibin B and inhibin A in tg-hpg females demonstrated that tg-FSH stimulated ovarian inhibin secretion (reviewed in Findlay et al. 2001). Elevated inhibin B supports our previous work showing that tg-FSH dose-dependently increased circulating inhibin B in hpg females (Allan et al. 2001), and confirm-ing the accepted role of FSH in stimulating granulosa cell inhibin B expression. Furthermore, our present work showed a significant correlation between serum inhibin B and predominantly the antral follicle populations. Likewise, elevated circulating inhibin A in tg-FSH hpg mice exhibiting antral follicle development, relative to non-tg hpg controls with antral arrest, agrees with the reported rise of inhibin A expression in secondary and antral follicles (Meunier et al. 1988, Wang et al. 2005). Inhibin A detection in 71% of tg-FSH (LH-deficient) hpg females in this study was similar to the 63% of LHR-null females expressing detectable inhibin A found by Hirst et al.(2004). Overall, these findings support recent studies showing increased serum inhibins B and A in FSH-treated hpg females to be associated with antral follicles, although higher inhibin A requires LH activity and the presence of preovulatory follicles (Wang et al. 2005).
The tg-FSH hpg ovary without LH stimulation would be expected to resemble ovaries in mice lacking functional LH-beta or receptor genes (Lei et al. 2001, Zhang et al. 2001, Ma et al. 2004), which previously provided valuable comparisons for testicular development (Zhang et al. 2001, Allan et al. 2004, Hirst et al. 2004). Indeed, arrested antral follicle development was observed in all these models exhibiting isolated FSH activity. Mice congenitally lacking the LH receptor exhibit elevated circulating gonadotrophins (Lei et al. 2001, Zhang et al. 2001) that are susceptible to steroidal regulation, which would complicate analysis of FSH actions combined with other hormones. In comparison, ectopic FSH expression in the tg-hpg model independent of GnRH and LH (Allan et al. 2004, Allan et al. 2001), as well as preserved hormone responsiveness, allows further investigation of FSH in isolation or combined with other hormones. The confounding effects of supraphysiological FSH concentrations previously reported in tg-FSH mice (Kumar et al. 1999) were not observed in this tg-FSH hpg model, since serum tg-FSH (4–5 IU/l) did not impede the fertility of young non-hpg females and was therefore within the limits compatible with physiological ovarian function (paper in preparation, Allan et al.).
In summary, our present study shows that FSH may enhance the early follicle stock. In isolation, tg-FSH activity increased the primordial pool relative to normal, despite predicted attrition through concurrent stimulation of antral follicle development and growth to the early preovulatory stage. Thus, the tg-FSH hpg ovary provides a valuable platform for exploration of the underlying molecular mechanisms that may orchestrate the development, survival or progression of the primordial follicle population. Future studies using this novel tg-FSH paradigm will explore the functional consequences of combined LH or steroidal actions upon follicle dynamics.
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Acknowledgements |
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Funding |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Received 14 December 2005
Accepted 19 December 2005
Made available online as an Accepted Preprint 21 December 2005
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