The Steroid Metabolome in the Isolated Ovarian Follicle and Its Response to Androgen Exposure and Antagonism.

The ovarian follicle is a major site of steroidogenesis, crucially required for normal ovarian function and female reproduction. Our understanding of androgen synthesis and metabolism in the developing follicle has been limited by the sensitivity and specificity issues of previously used assays. Here we used liquid chromatography-tandem mass spectrometry to map the stage-dependent endogenous steroid metabolome in an encapsulated in vitro follicle growth system, from murine secondary through antral follicles. Furthermore, follicles were cultured in the presence of androgen precursors, nonaromatizable active androgen, and androgen receptor (AR) antagonists to assess effects on steroidogenesis and follicle development. Cultured follicles showed a stage-dependent increase in endogenous androgen, estrogen, and progesterone production, and incubations with the sex steroid precursor dehydroepiandrosterone revealed the follicle as capable of active androgen synthesis at early developmental stages. Androgen exposure and antagonism demonstrated AR-mediated effects on follicle growth and antrum formation that followed a biphasic pattern, with low levels of androgens inducing more rapid follicle maturation and high doses inhibiting oocyte maturation and follicle growth. Crucially, our study provides evidence for an intrafollicular feedback circuit regulating steroidogenesis, with decreased follicle androgen synthesis after exogenous androgen exposure and increased androgen output after additional AR antagonist treatment. We propose that this feedback circuit helps maintain an equilibrium of androgen exposure in the developing follicle. The observed biphasic response of follicle growth and function in increasing androgen supplementations has implications for our understanding of polycystic ovary syndrome pathophysiology and the dose-dependent utility of androgens in in vitro fertilization settings.

What is the best diagnostic and therapeutic management strategy for an Addison patient during pregnancy?

A new diagnosis of primary adrenal insufficiency (PAI) during pregnancy is extremely rare and difficult to recognize as signs and symptoms such as nausea, fatigue and hypotension may resemble features of normal pregnancy. However, if the diagnosis is overlooked and steroid replacement delayed, subsequent adrenal crisis triggered by hyperemesis gravidarum, fever or delivery can cause severe maternal and foetal morbidity and even mortality. In case of clinical suspicion of PAI, we recommend to measure paired samples of cortisol and ACTH and, if clinically feasible, a short synacthen test. We propose trimester-specific pass cut-offs for the short synacthen test that take into account the rise of total and also free cortisol during pregnancy. Empirical hydrocortisone treatment should never be delayed if the clinical suspicion is high. All pregnant women with PAI should be monitored by a team of endocrine and obstetric specialists. The third trimester is physiologically associated with a rise not only in total but also free cortisol and thus requires regular adjustment of the glucocorticoid dose. Mineralocorticoid requirements may change during pregnancy due to the anti-mineralocorticoid properties of progesterone. As plasma renin physiologically increases in pregnancy, monitoring is limited to clinical assessment including blood pressure and serum electrolytes. It is crucial that a pregnant woman with PAI and her partner are well educated regarding the adjustment of glucocorticoid dose in intercurrent illness and that both are trained in hydrocortisone emergency injection techniques. The obstetric staff should be provided with clear and written guidance for hydrocortisone cover during labour and delivery. With the appropriate replacement therapy, PAI patients can expect to have an uneventful pregnancy and deliver a healthy infant.

Androgen replacement therapy in women.

Female androgens are derived from either the adrenal and peripheral conversion of the adrenal sex steroid precursor, dehydroepiandrosterone, or from direct ovarian production. Adrenal insufficiency or bilateral oophorectomy (surgical menopause) result in severe androgen deficiency, which can be clinically associated with impaired libido, drive and energy. Physiological menopause does not necessarily lead to androgen deficiency. The previously suggested definition of female androgen deficiency syndrome, as the concurrent presence of low androgen levels and low libido, is not precise enough and may lead to overdiagnosis. Current replacement options include transdermal testosterone or oral dehydroepiandrosterone treatment, both of which have been shown to result in significant improvements, in particular in libido and mood, while long-term effects on body composition, cardiovascular and cancer risk are less documented. Owing to these concerns, androgen replacement should be reserved for women with severe androgen deficiency due to an established cause and matching clinical symptoms.

Outcome of 100 pregnancies initiated under treatment with cabergoline in hyperprolactinaemic women.

CONTEXT: Data concerning the safety for pregnancy of cabergoline treatment in hyperprolactinaemic women are still scarce. OBJECTIVE: To exclude a higher than normal risk for miscarriage and congenital malformation in pregnancies initiated under cabergoline treatment. DESIGN: A retrospective study of 100 pregnancies in 72 hyperprolactinaemic women treated with cabergoline at the time of conception and follow-up of the 88 newborn children. METHODS: Cabergoline was interrupted in 99 pregnancies and continued in one case. Foetal exposure dose to cabergoline was calculated for each pregnancy. Complications of pregnancy and neonatal status were compared to those observed in an age-and delivery time-matched control group of 163 women. RESULTS: The mean foetal exposure dose to cabergoline was 3.6 +/- 4.7 mg. The rate of spontaneous miscarriages was 10%. Three medical terminations of pregnancy were performed for a foetal malformation (3%). Minor to moderate complications were observed in 31% of the pregnancies, a figure similar to that found in the control group. An increase in tumour size (2-8 mm) was observed in 17/37 evaluated cases, needing reintroduction of cabergoline during pregnancy in five patients. The 84 deliveries resulted in 88 infants, three of them presenting with a malformation (3.4%). Neonatal status was comparable to the control group, where a malformation rate of 6.3% was observed. Postnatal development of the children was normal. CONCLUSION: Cabergoline treatment at the time of conception appears to be safe for both the pregnancy and the neonate, although more data are still needed on a larger number of pregnancies.