Marianne J. Reymond

Androgen dependence of hirsutism, acne, and alopecia in women: retrospective analysis of 228 patients investigated for hyperandrogenism.

Hirsutism, acne, alopecia, and oligo-amenorrhea are clinical expressions of hyperandrogenism, one of the most frequent endocrine disorders in women of reproductive age. Women referred to our endocrine clinics for skin symptoms of hyperandrogenism underwent a laboratory workup to evaluate hormone measurements and received antiandrogen therapy. We retrospectively analyzed the outcome of 228 consecutive patients investigated over 6 years. Patients with hirsutism had higher levels of androstenedione, dehydroepiandrosterone sulfate (DHEAS), and salivary testosterone; lower levels of sex hormone-binding globulin (SHBG); and a higher prevalence of oligo-amenorrhea than patients with alopecia, while patients with acne showed intermediate values. Hirsutism score correlated positively with androstenedione, DHEAS, and salivary testosterone, and correlated negatively with SHBG; salivary testosterone showed the highest correlation coefficient. Total testosterone was not significantly different among patients with hirsutism, alopecia, or acne, and did not significantly correlate with hirsutism score. Hirsutism and oligo-amenorrhea were the most sensitive symptoms of hyperandrogenism, and no androgenic parameter alone allowed us to identify all cases of hyperandrogenism. Patients of central European origin sought consultation with milder hirsutism scores than patients of southern European origin. There was, however, no difference in the clinical-biological correlation between these groups, arguing against differences in skin sensitivity to androgens. Polycystic ovary syndrome, defined as hyperandrogenism (hirsutism or elevated androgens) and oligo-amenorrhea, was diagnosed in 63 patients (27.6%), an underestimate compared with other reports that include systematic ovarian ultrasound studies. Neither pelvic ultrasound, used in a limited number of cases, nor the luteinizing hormone/follicle-stimulating hormone ratio helped to distinguish patients with polycystic ovary syndrome from the other diagnostic groups. These included hyperandrogenism (hirsutism or elevated androgens) and eumenorrhea (101 patients; 44.3%); normal androgens (acne or alopecia and eumenorrhea) (51 patients; 22.4%); isolated low SHBG (7 patients; 3.1%); nonclassical congenital adrenal hyperplasia (4 patients; 1.8% of total, 4.9% of patients undergoing cosyntropin stimulation tests); and ovarian tumor (2 patients; 0.9%). Ethinylestradiol and high-dose cyproterone acetate treatment lowered the hirsutism score to 53.5% of baseline at 1 year, and was also effective in treating acne and alopecia. The clinical benefit is ascribed to the peripheral antiandrogenic effect of cyproterone acetate as well as the hormone-suppressive effect of this combination. Salivary testosterone showed the most marked proportional decrease of all the androgens under treatment. Cost-effectiveness and tolerance of ethinylestradiol and high-dose cyproterone acetate compared well with other antiandrogenic drug therapies for hirsutism. The less potent therapy with spironolactone only, a peripheral antiandrogen without hormone-suppressive effect, was effective in treating isolated alopecia in patients with normal androgens. Abbreviations: 17-OHP = 17-hydroxyprogesterone, DHEA = dehydroepiandrosterone, DHEAS = dehydroepiandrosterone sulphate, FSH = follicle-stimulating hormone, LH = luteinizing hormone, NCAH = nonclassical congenital adrenal hyperplasia, SHBG = sex hormone-binding globulin.

The Secretory Activity of the Tuberoinfundibular Dopaminergic Neurons Is Modulated by the Thyroid Status in the Adult Rat: Consequence on Prolactin Secretion

An influence of thyroid status on the secretory activity of hypothalamic dopaminergic neurons was observed in adult rats and its involvement in the regulation of prolactin (PRL) secretion was examined. The secretory activity of the tuberoinfundibular dopaminergic (TIDA) neurons was evaluated by measurement of dopamine (DA) biosynthesis in the neurons and DA release into hypophysial portal blood. The accumulation of DA and PRL in the adenohypophysis as well as PRL concentration in plasma were also estimated, and the various parameters were studied in thyroidectomized (TX), sham TX, TX rats treated for 7 days with thyroxine (T4; 20 micrograms/kg body weight daily) as well as in intact rats treated similarly with T4. An enhanced secretory activity of the TIDA neurons was observed in TX compared to sham TX rats, as attested by an increased synthesis of DA in the neurons, a greater concentration of DA in hypophysial portal plasma as well as an augmented accumulation of DA in the adenohypophysis. In the same animals, PRL was reduced in the adenohypophysis and in plasma, reflecting a blunted secretion of PRL in severe hypothyroidism. Treatment of TX rats with T4 for 7 days abolished all effects observed in TX rats, DA synthesis in TIDA neurons of TX rats treated with T4 being even less than in neurons of sham TX animals. A similar treatment with T4 administered to intact rats did not affect the secretory activity of the TIDA neurons nor the secretion of PRL.(ABSTRACT TRUNCATED AT 250 WORDS)

Follicle-stimulating hormone bioactivity in idiopathic normogonadotropic oligoasthenozoospermia: double-blind trial with gonadotropin-releasing hormone*

OBJECTIVE To identify, among patients with idiopathic normogonadotropic oligoasthenozoospermia, those with low bioactive follicle-stimulating hormone (FSH), possibly because of inadequate gonadotropin-releasing hormone (GnRH) pulsatility, whose bioactive FSH and sperm could be improved by GnRH treatment. DESIGN Randomized, double-blind, placebo-controlled trial with intranasal (IN) GnRH, followed by open GnRH treatment. SETTING Outpatient endocrinology clinic. PATIENTS Twenty-eight infertile men with idiopathic normogonadotropic oligoasthenozoospermia. INTERVENTIONS Gonadotropin-releasing hormone or placebo was self-administered IN every 2 hours. MAIN OUTCOME MEASURES Serum immunoreactive and bioactive FSH and semen analyses. RESULTS Ten men showed a low basal FSH bioactive/immunoreactive ratio, which increased in 5 of them under GnRH without parallel sperm modification. Sperm improvements were observed in 10 patients with no parallel evolution of FSH bioactive/immunoreactive ratio. Unpredicted by sperm changes, three pregnancies developed on placebo and 5 on GnRH. CONCLUSIONS Low bioactive FSH was not the cause of idiopathic normogonadotropic oligoasthenozoospermia in our patients and could not predict response to GnRH. Pulsatile GnRH did not improve sperm beyond random fluctuations.

Thyroid and pituitary secretory disorders in streptozotocin-diabetic rats are associated with severe structural changes of these glands

SummaryStreptozotocin diabetes in rats is associated with reduced function of the hypothalamopituitary-thyroid axis. The structure and hormone secretion of the thyroid and pituitary glands were studied in adult male rats 1 month after streptozotocin injection. The thyroid of diabetic rats was characterized by decreased follicle area and epithelial thickness. By electron microscopy, thyroid epithelial cells were characterized by flattened and almost empty rough endoplasmic reticulum cisternae, scanty exocytotic apical and endocytotic vesicles as well as degenerate mitochondria and rough endoplasmic reticulum. By immunohistochemistry, intracolloidal thyroglobulin and T3 as well as intraepithelial thyroglobulin were reduced. Electron microscopic and immunohistochemical analysis of pituitary glands showed that in diabetic rats thyrotrophs were mostly of type II, and the number of thyrotrophs (type I + type II) was greater than in controls. By radioimmunoassay (RIA), plasma T3, T4, and TSH levels were markedly reduced, and the TSH response to TRH was deficient in diabetic animals. The pituitary TSH concentration was increased, as expected from the morphological data. This study demonstrates severe structural changes in the thyroid and pituitary glands of diabetic rats which are accompanied by marked alterations of their secretory activity.

Hypothalamic-hypophysial vasculature and its relationship to secretory cells of the hypothalamus and pituitary gland

Publisher Summary This chapter discusses the development of hypothalamic-hypophysial vasculature and its relationship to secretory cells of the hypothalamus and pituitary gland. The sinusoids of the pars distalis of the pituitary gland and the capillaries in the floor of the ventricular recess of the third ventricle are connected through veins that lie on the surface of the pituitary stalk. The venous drainage of the neurohypophysis, by way of veins, connects the pars neuralis with the cavernous sinus and by way of portal vessels connects the median eminence and pituitary stalk with the pars distalis. The pars distalis of the adenohypophysis receives only venous blood by way of hypophysial portal vessels. The primary capillary plexus of the portal vessels lies in the median eminence and pituitary stalk; the secondary capillary plexus of these vessels lies in the pars distalis. Neurosecretory cells, lying within diffusion distances of the primary capillary plexus of the portal vessels, secrete products that diffuse into the blood of the portal vessels. Some pituitary hormones act on neurons of the hypothalamus to alter their activity.

Neuroendocrine Aspects of Aging: Experimental Data

Aging is characterized by changes in neuroendocrine/endocrine functions which are manifest in female reproductive physiology and less perceptible in other functions such as thyroid, adrenal or growth/metabolic functions. The contribution of each level of the axis - hypothalamus, adenohypophysis or peripheral tissues - is not clearly established. Functional impairments with age are recognized in the peripheral glands (gonad, thyroid, adrenal) as well as in the pituitary, but increasing evidence is accumulating for a marked contribution of the hypothalamus in the age-associated endocrine changes observed in animals and humans. In old rats, multineuronal dysfunctions are demonstrated in the hypothalamus, with a documented decline in the activity of the neurons producing dopamine and thyrotropin-releasing hormone, and to a lesser extent luteinizing hormone- and growth hormone-releasing hormones, and alterations in regulatory mechanisms of these neurons are disclosed. Moreover, impairments are observed in the processing - binding, accumulation and intracellular distribution - of hypothalamic hormones in the adenohypophysis of old rats. Taken together, these observations are supportive of the view that the neuroendocrine/endocrine changes appearing with age result from a complex balance of functional alterations occurring at each level - central and peripheral - of the axis.

Functional and Morphological Changes in Mediobasal Hypothalamus of Streptozocin-induced Diabetic Rats: In Vitro Study of LHRH Release

To investigate the role of the mediobasal hypothalamus (MBH) in diabetic gonadal axis disorders, the MBHs of adult male streptozocin-induced diabetic (STZ-D) rats were examined after incubation in basal conditions or in K+-enriched medium and compared with those of controls. Diabetes lasted 1 mo. Both luteinizing-hormone-releasing hormone (LHRH) release and MBH morphology were studied. After incubation in basal conditions, the LHRH release was unchanged. By light microscopy, the dilated-axon cross sections were more numerous (P < .01) in the basal arcuate nucleus and in the median eminence. By electron microscopy, the ratio of exocytoses to neurosecretory granules observed in the median eminence axon cross sections was smaller (P < .05). The total LHRH immunoreactivity, the number of labeled axons, and the amount of positive material in the axons were reduced (P < .05). After incubation in K+-enriched medium, the LHRH release was markedly reduced (P < .01). The number and area of dilated-axon cross sections, possibly because of the relation between exocytosis and physiological dilation, were less augmented (P < .01). Whereas the number of exocytoses and the ratio of exocytoses to neurosecretory granules were not decreased, the total LHRH immunoreactivity and the number of labeled axons were reduced (P < .05). The releasable LHRH pool therefore seems to be exhausted in control MBH because of long-term stimulation and reduced in the MBH of STZ-D rats because of diabetes. In conclusion, STZ-D causes functional and anatomical MBH lesions that should be pathogenetically relevant for the disorders of the gonadal axis documented in this animal model.

Some aspects of hypothalamic and hypophysial secretion in aging rats

Abstract The quantity as well as concentration of dopamine in the hypothalamus of the aged rat is about half that in the hypothalamus of the young rat. The reduction in hypothalamic dopamine in old rats is associated with a reduction in the hypothalamic turnover and secretion of dopamine into hypophysial portal blood. The reduced ability of aged animals to secrete dopamine may be due to: (a) a reduction in the number of dopaminergic neurons in the hypothalamus, (b) an inability of the dopaminergic neurons to respond adequately to stimulation, and/or (c) an increase in the rate of secretion of substances, e.g. , β-endorphin and 5-hydroxytryptamine, that inhibit dopamine secretion. In contrast to the secretion of dopamine by the hypothalamus, the secretion of prolactin by the hypophysis is greater in aged animals than in young animals. This increased secretion may be due to the reduced concentration of dopamine in portal blood and/or the loss of ability of prolactin cells in the aged hypophysis to process and respond to dopamine.

Influence of Age on the Control of Thyrotropin Secretion by Thyrotropin-Releasing Hormone in the Male Rat

Alterations with age in the control of thyrotropin (TSH) secretion by thyrotropin-releasing hormone (TRH) were evaluated at the hypothalamic and pituitary levels in young (3-5 months) and old (22-24 months) male rats. In the hypothalamus, TRH was quantified in the median eminence and in the mediobasal hypothalamus; in the adenohypophysis the membrane receptors for TRH were evaluated as well as the accumulation of TRH in the gland. As for TSH, its concentration was determined in the anterior pituitary gland and in plasma. In the hypothalamus, the concentration of TRH did not differ between young and old rats in the whole mediobasal hypothalamus, but it was significantly less in the old rats at the level of the median eminence (29.9 +/- 2.8 vs. 52.2 +/- 4.3 ng/mg protein). In the adenohypophysis, the density of receptors for TRH was greater in the old than in the young rats (23.2 +/- 3.2 vs. 13.7 +/- 1.1 fmol MeTRH/mg gland)--with no change in the affinity constant--, and the amount of TRH detected was larger (10.8 +/- 1.8 vs. 2.8 +/- 0.6 pg/mg gland), illustrative of an age-related increase in TRH accumulation in the pituitary gland. The latter results are contrasting with the findings of unchanged pituitary and plasma concentrations of TSH as well as unmodified TSH response to TRH in old rats. The present data concerning TRH and the analogy with previous observations regarding dopamine in old rats are indicative of reduced neuronal activities with age at the hypothalamic level associated with impairments in the processing of the hypothalamic hormones at the pituitary level.

Tuberoinfundibular dopaminergic neurons and lactotropes in young and old female rats.

Aging in female rats is accompanied by several endocrine dysfunctions, such as reproductive decline associated with characteristic hyperprolactinemia, lactotrope hyperplasia, and functional impairment of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons. The aim of this morphometrical, immunocytochemical, and densitometrical study was to gain a better anatomical knowledge of TIDA neurons and axons as well as of lactotropes in old female rats with (A) or without (NA) pituitary adenomas, compared with young animals. At the hypothalamic level, we found that tyrosine hydroxylase (TH)-labeled neurons in the arcuate nucleus were comparable in young and old NA yet their size and TH-content were increased in A animals. Also the TH-labeled median eminence axons did not differ significantly between young and old NA but were more numerous in the old A rats. Independently from adenomas, both number of prolactin (PRL)-labeled structures and content of immunoreactive PRL were increased in pituitaries of old rats, the plasma PRL levels, however, were high only in A. Our findings support the documented lactotrope hypertrophy and hyperplasia in old female rats and suggest that TIDA-neuron changes only occur in hyperprolactinemic animals carrier of adenomas.