Page 734 - Basic _ Clinical Pharmacology ( PDFDrive )

40 The Gonadal Hormones
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& Inhibitors

George P. Chrousos, MD

C ASE STUD Y

A 25-year-old woman with menarche at 13 years and with premature ovarian failure, and estrogen and pro-
menstrual periods until about 1 year ago complains of hot gesterone replacement therapy is recommended. A dual-
flushes, skin and vaginal dryness, weakness, poor sleep, and energy absorptiometry scan (DEXA) reveals a bone density
scanty and infrequent menstrual periods of a year’s dura- t-score of <2.5 SD, ie, frank osteoporosis. How should the
tion. She visits her gynecologist, who obtains plasma levels ovarian hormones she lacks be replaced? What extra mea-
of follicle-stimulating hormone and luteinizing hormone, sures should she take for her osteoporosis while receiving
both of which are moderately elevated. She is diagnosed treatment?

■ THE OVARY (ESTROGENS, hormone (GnRH). Despite extensive research in the field, the
PROGESTINS, OTHER mechanism of puberty initiation still remains an enigma. Pulsatile
pituitary gonadotropin secretion under the guidance of GnRH
OVARIAN HORMONES, ORAL definitely constitutes a sine qua non for pubertal onset. However,
CONTRACEPTIVES, INHIBITORS the secretion of GnRH in the human hypothalamus is regulated
by kisspeptin and its receptor, as well as by permissive or opposing
& ANTAGONISTS, & OVULATION- signals mediated by neurokinin B and dynorphin acting on their
INDUCING AGENTS) respective receptors. These three supra-GnRH regulators com-
pose the Kisspeptin, Neurokinin B, and Dynorphin neuron
The ovary has important gametogenic functions that are inte- (KNDy) system, a key player in pubertal onset and progression.
grated with its hormonal activity. In the human female, the Recently, makorin ring finger protein 3 (MKRN3) was also
gonad is relatively quiescent during childhood, the period of implicated in pubertal onset by contributing to the regulation
rapid growth and maturation. At puberty, the ovary begins a of the KNDy system. However, the inhibitory (gamma-amino
30- to 40-year period of cyclic function called the menstrual butyric acid, neuropeptide Y, and RFamide-related peptide-3)
cycle because of the regular episodes of bleeding that are its most and stimulatory (glutamate) signals acting upstream of KNDy call
obvious manifestation. It then fails to respond to gonadotropins into question the primary role of MKRN3 as the gatekeeper of
secreted by the anterior pituitary gland, and the cessation of cyclic puberty. Recently, epigenetic mechanisms involving derepression
bleeding that occurs is called menopause. of genes, such as that of kisspeptin, have been implicated in puber-
The mechanism responsible for the onset of ovarian func- tal onset. Ultimately, withdrawal of a childhood-related inhibitory
tion at the time of puberty is thought to be neural in origin, effect upon hypothalamic arcuate nucleus neurons allows these
because the immature gonad can be stimulated by gonadotro- neurons to produce GnRH in pulses with the appropriate ampli-
pins already present in the pituitary and because the pituitary is tude, which stimulate the release of follicle-stimulating hormone
responsive to exogenous hypothalamic gonadotropin-releasing (FSH) and luteinizing hormone (LH) (see Chapter 37). At first,

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