Female Offspring From Chronic Hyperandrogenemic Dams Exhibit Delayed Puberty and Impaired Ovarian Reserve - PubMed (original) (raw)

Female Offspring From Chronic Hyperandrogenemic Dams Exhibit Delayed Puberty and Impaired Ovarian Reserve

Zhiqiang Wang et al. Endocrinology. 2018.

Abstract

Female offspring of many species exposed to high doses of androgens in utero experience endocrine dysfunction during adulthood. The phenotype of offspring from females with prepregnancy hyperandrogenemia and impaired ovulation, however, has not been examined. We developed a mouse model of hyperandrogenemia by implanting a low-dose dihydrotestosterone (DHT) pellet 15 days before conception. Female offspring born to dams with hyperandrogenemia (DHT daughters) had delayed puberty (P < 0.05) with first estrus on postnatal day (PND) 41 compared with daughters from dams with physiological levels of DHT (non-DHT daughters, PND37.5). Serum follicle-stimulating hormone (FSH) levels in the DHT daughters were fourfold higher (P < 0.05) on PND21, and anti-Müllerian hormone levels were higher (P < 0.05) on PND26 than in non-DHT daughters (controls). DHT daughters showed an extended time in metestrus/diestrus and a shorter time in the proestrus/estrus phase compared with non-DHT daughters (P < 0.05). To examine ovarian response to gonadotropins, superovulation was induced and in vitro fertilization (IVF) was performed. Fewer numbers of oocytes were retrieved from the DHT daughters compared with non-DHT daughters (P < 0.05). At IVF, there was no difference in rates of fertilization or cleavage of oocytes from either group. There were fewer (P < 0.01) primordial follicles (6.5 ± 0.8 vs 14.5 ± 2.1 per ovary) in the ovaries of DHT daughters compared with non-DHT daughters. Daughters from hyperandrogenemic females exhibited elevated prepubertal FSH levels, diminished ovarian response to superovulation, impaired estrous cyclicity, delayed onset of puberty, and reduced ovarian reserve, suggesting that fetal androgen exposure had lasting effects on female reproductive function.

Copyright © 2018 Endocrine Society.

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Figures

Figure 1.

Figure 1.

(A) Schematic diagram of the study. Numbers above the timeline represent days before birth (−) or postnatal days. Tests are listed below the timeline at times performed. (B) Serum DHT levels (_y_-axis) of control (open bars) and DHT-implanted (black bars) female mice before and during pregnancy. Values are mean ± standard error of the mean. n = 5 to 8 per group.

Figure 2.

Figure 2.

Prepregnancy maternal DHT treatment resulted in reduced body weight in female offspring. Body weight (_y_-axis) was measured on postnatal days, as shown (_x_-axis). *Represents significant difference (P < 0.05); **P < 0.01; ***P < 0.001 at each time point. Values are mean ± standard error of the mean. n = 9 to 14 per group. control, circles; DHT-exposed offspring, squares.

Figure 3.

Figure 3.

Prepregnant maternal DHT treatment delayed the onset of puberty in female offspring. (A) Vaginal opening noted by daily assessment (_y_-axis) in control pellet (non-DHT; open bars) or DHT-exposed offspring (black bars). (B) Day at first E as assessed by vaginal cytology (_y_-axis) in control (open bars) or DHT-exposed (black bars) offspring. Values are mean ± standard error of the mean. n = 4 to 13 per group. NS, not significant.

Figure 4.

Figure 4.

Hormone levels during prepubertal/peripuberty. Blood was collected at PNDs 21 and 26 in the morning at M/D stage. (A) Serum estradiol levels were measured by ELISA (Calbiotech), (B) serum LH, (C) serum FSH, and (D) serum AMH levels. Values are mean ± standard error of the mean. n = 5 to 11 per group. For (A)–(E): control pellet (non-DHT; open bars) or DHT-exposed offspring (black bars). NS, not significant.

Figure 5.

Figure 5.

Hormone levels at PND70. (A) Serum T levels. (B) Serum estradiol levels measured by ELISA (Calbiotech, Inc.). (C) Serum AMH levels. (D) Serum levels of LH and FSH at different stages of the estrous cycle. Values are mean ± standard error of the mean. n = 5 to 11 per group. For (A)–(D): control pellet (non-DHT; open bars) or DHT-exposed offspring (black bars). NS, not significant; P/E, proestrus/estrus.

Figure 6.

Figure 6.

Chronic maternal androgen excess leads to disturbed cyclicity in adult daughters. (A) The total completed E cycles (_y_-axis) within 15 days as measured by cytology. _x_-axis = number of cycles. (B) The percentage of time spent at each estrous stage (_y_-axis) was analyzed. Values are mean ± standard error of the mean. n = 5 to 9 per group. Values are mean ± standard error of the mean. Control pellet (non-DHT; open bars) or DHT-exposed offspring (black bars). P/E, proestrus/estrus.

Figure 7.

Figure 7.

IVF and ovarian follicle counts. IVF was performed with the DHT daughter and non-DHT daughter mice. (A) The total number of retrieved oocytes and mature eggs (_x_-axis) after superovulation, which were counted (_y_-axis) from two ovaries per mouse. (B) The percentages (_y_-axis) of fertilized oocytes (number of fertilized oocytes divided mature oocytes) and cleavage stage embryos (≥2 cells stage; number of embryos divided fertilized oocytes; _x_-axis) are shown for treated and control groups. (C) Total numbers of follicles (_y_-axis) of different stages in the ovarian sections (see Materials and Methods) after superovulation were quantified as primordial, primary, secondary, or antral (_x_-axis). CL were not determined for these sections. (D) Total numbers of follicles (_y_-axis) were quantified in the ovarian sections from mice that had not undergone superovulation. Values are mean ± standard error of the mean. n = 5 to 13 per group. NS, not significant.

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